Design
Observational cohort study of HIV-infected patients in Canada and the United States.
Population
Over 8,300 HIV-infected patients with CD4+ cell counts between 351 to 500 cells/mm3.
Main Results
Starting HIV therapy at a CD4+ cell count greater than 350 cells/mm3 was associated with a 70% improvement in survival (RH: 1.7; 95% CI, 1.4-2.1; P < .001) -- an effect that persisted even after adjusting for factors associated with impaired survival (e.g., injection drug use, HCV coinfection).
Significance
Indicates that a starting threshold for HIV therapy of 350 cells/mm3 is too low and, more importantly, that deaths can be prevented with earlier initiation of HIV therapy.
Design
A pair of investigations were conducted: (1) a nested case-control study of HIV-infected INSIGHT SMART participants for studying biomarker associations with mortality, and (2) a study to compare drug conservation versus viral suppression participants for biomarker changes.
Population
(1) 85 participants who died (55 were in the discontinuation of HIV therapy arm, the remainder in the continuation arm) compared to two controls who did not die per each case. (2) About 250 participants without known prior CVD.
Main Results
The combined results show that, at baseline, the levels of almost all markers were higher in patients who died (cases) than in the controls. IL-6 and D-dimer stood out as most significantly different between patients who died and those who did not. Based on models of mortality risk generated from the baseline biomarker data, the differences in the change in levels in the study arms are predicted to lead to a 16% to 24% increased risk of death for those stopping antiretroviral therapy.
Significance
Both investigations pin an attractively reasonable causative mechanism to the potentially catastrophic effects of treatment cessation. Point to a new way to view the threats to the well-being of patients who, despite robust immune function, have suboptimally controlled HIV infection. Irrevocably establish endothelial dysfunction as a dimension of the management of HIV disease.
Design
International, prospective, observational cohort study assessing the risk of MI among patients exposed to NRTIs.
Population
33,347 HIV-infected patients from 188 clinics in 21 countries in Europe, the United States and Australia.
Main Results
Over 157,912 person-years. 517 patients had a MI. Rates of MI were 90% and 49% greater among patients who had recent exposure to abacavir or didanosine, respectively, relative to those without recent use of these agents.
Significance
Results showed abacavir and didanosine increase MI risk. Excess risk did not seem to be explained by underlying established cardiovascular risk factors and was not present beyond six months after drug cessation.
Design
Randomized, placebo-controlled trial of abacavir/lamivudine vs. tenofovir/emtricitabine co-administered with either ritonavir-boosted atazanavir or efavirenz.
Population
1,858 HIV-infected patients; 797 had screening HIV-RNA ≥ 100,000 copies/mL.
Main Results
Those who had been assigned to abacavir/lamivudine had a greater risk of failure (HR = 2.33; 95% CI, 1.46-3.72; P < .01) compared to those who had been assigned to tenofovir/emtricitabine.
Significance
Results showed a significantly shorter time to virologic failure and grade 3/4 adverse events in patients randomized to abacavir/lamivudine. Comparisons of blinded NRTIs in the lower HIV-RNA stratum and each regimen's third drug in both strata are ongoing.
Design
Randomized, double-blind, placebo-matched, multi-center, 96-week, non-inferiority study. Patients received either blinded abacavir/lamivudine or tenofovir/emtricitabine with open-label lopinavir/ritonavir soft gel capsule once daily.
Population
688 HIV-1-infected, antiretroviral-naive patients had a plasma HIV-1 RNA ≥ 1,000 copies/mL, (stratified < or ≥ 100,000 copies/mL), and any CD4+ count. Mean age was 38 years; 18% were female.
Main Results
No significant difference in virologic efficacy between the two study arms. Levels of hs-CRP and IL-6 fall in a similar manner in both study arms during the course of the trial.
Significance
Contradicts A5202 findings that showed a significantly shorter time to virologic failure and grade 3/4 adverse events in patients randomized to abacavir/lamivudine.
Design
Exploratory study of biomarkers, ischemic changes on the electrocardiogram and rates of various predefined types of CVD events according to NRTIs used in SMART study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine.
Population
2,752 participants in the continuous drug therapy arm of the SMART trial.
Main Results
Abacavir -- but not didanosine -- was associated with various definitions of CVD. As in the D:A:D study, the deleterious impact of abacavir was greatest in patients who had greater CVD risk.
Significance
Showed abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event.
Design
Pooled summary of 54 industry-sponsored trials with ≥ 24 weeks of combination antiretroviral therapy (CART) with and without abacavir.
Population
14,683 HIV-infected patients who received abacavir-containing CART (N = 9,639; 7,845 person-years) or non-abacavir-containing CART (N = 5,044; 4,653 person-years).
Main Results
No higher risk of myocardial infarction associated with abacavir-containing CART was identified in this review.
Significance
Contradicts D:A:D and A5202 study results.
Design
Pooled summary of 48-week efficacy data from six clinical trials of abacavir/lamivudine using the A5202 definitions of virologic failure.
Population
2,940 antiretroviral-naive patients.
Main Results
High rates of efficacy with abacavir/lamivudine and minimal difference in treatment response by baseline viral load.
Significance
Contradicts D:A:D and A5202 study results.
Design
Case study.
Population
40-year-old man in Germany with HIV-1 infection since 1995 having a relapse of acute myeloid leukemia first diagnosed in 2006.
Main Results
More than 600 days post-transplant, the patient has undetectable levels of HIV in his peripheral blood, bone marrow and rectal mucosa. The patient's CD4+ cells continue to be absent CCR5 receptors.
Significance
Given the cost and the high risk of life-threatening complications, stem cell transplantation is not the HIV cure we need, or want. However, the results suggest that less dramatic and risky interventions are well worth exploring; these include such things as gene therapy to alter lymphocyte co-receptor expression.
Design
Randomized, double-blind, non-inferiority clinical trial of raltegravir vs. efavirenz, when taken with tenofovir/emtricitabine, among HIV-infected, treatment-naive patients.
Population
563 patients, randomized 1:1 to each treatment arm. Trial participants were mostly male and non-white.
Main Results
At week 48, 86% of patients who had been randomized to raltegravir compared to 82% who had been assigned to efavirenz achieved a viral load < 50 copies/mL -- a 4% difference meeting the condition for non-inferiority. CD4+ cell count gains were seen in both arms with a statistically significantly greater increase seen with raltegravir than efavirenz (189 cells/mm3 vs. 163 cells/mm3, respectively).
Significance
Viral load responses for raltegravir were comparable with that of efavirenz and tolerability was better overall. Further studies will determine if this agent can be administered once a day. A "New Drug Application" has been filed with the U.S. Food and Drug Administration for a treatment-naive indication for raltegravir and an outcome is expected this summer.
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
740 patients who were treatment-naive and harboring R5-only virus at screening.
Main Results
At 48 weeks, 65.3% of the patients who were taking maraviroc had a viral load < 50 copies/mL vs. 69.3% of those who were treated with efavirenz (everyone got zidovudine/lamivudine). The difference was 4.2%, with a lower limit bounds of the 97.5% CI that just exceeded the outer bounds for non-inferiority of 10%. If those with dual/mixed virus detected during the study are excluded, the difference in the proportion with a viral load of < 50 copies/mL narrows between the arms. If the participants with previously unrecognized non-R5 virus are excluded from the primary analysis, an identical 68% of those in both arms get a viral load < 50 copies/mL at week 48.
Significance
These post hoc analyses may soften the stance that this drug is not a contender for first-line status and sway some providers.
Design
Randomized, phase 4 strategy trial of giving HIV therapy during acute treatment of OI (within 14 days of OI diagnosis and 48 hours of study entry) vs. deferral of treatment until after initial treatment of OI.
Population
282 people with AIDS and treatable OIs (tuberculosis was an exclusion criterion) or bacterial infections.
Main Results
At 48 weeks, the immediate treatment group had a 14.2% reduced rate of AIDS progression or death compared with the deferred treatment group (24.1%) (HR = 0.53; 99% CI, 0.25-1.09; P = .023).
Significance
Supports the early application of HIV therapy during acute OIs and bacterial infections to shorten the period of vulnerability to life-threatening AIDS progression. Concerns for IRIS are justified, but these data indicate that the benefits of antiretrovirals trump the risk of immune reconstitution complications in the setting of these OIs.
Design
Evaluation of the implementation of the CDC's recommendations for opt-out HIV testing in the United States.
Main Results
Concerns about the change include laws in some states that mandate signed consent and counseling, a perception that counseling is an effective prevention strategy, variability in payment coverage for the test, concerns about the stigma and discrimination that may accompany the HIV diagnosis, and the possibility that other testing policies would be more effective. Eleven of 16 states have changed legislation to reduce barriers to testing, 35 of 74 national professional societies have endorsed the new recommendations, and multiple demonstration projects have shown feasibility. Metrics to evaluate the health outcomes have been defined, but the data necessary to determine the effects on early entry into care, the actual reduction in disease incidence, and the unanticipated consequences are not yet available.
Significance
Increased screening will identify those with HIV, allowing them to enter care and treatment early, thus improving their health while reducing their infectiousness and (hopefully) their risk behaviors. Opt-out testing is a streamlined process that allows routine HIV testing to become routine.
Design
Evaluation of the effect of the new opt-out policy on uptake of HIV testing and positivity rate and identified factors associated with actively declining the HIV test.
Population
Patients who presented for HIV testing at the STI outpatient clinic in Amsterdam, The Netherlands, (average of 24,000 consultations/year) in 2006 and 2007.
Main Results
In 2006, prior to the implementation of the new testing policy in January 2007, 1,534/4,024 (38%) MSM patients and 5,254/19,341 (27%) heterosexual patients did not test for HIV. In 2007, however, only 12% (470/3,865) of MSM and 4% (837/21,305) of heterosexuals opted-out of HIV testing. The proportion of patients with a positive HIV test remained constant during both time periods (~3.5% of MSM and ~0.25% of heterosexuals tested positive), meaning that with the increased numbers tested and unchanged infection rates, more people with HIV were detected with the change to opt-out testing.
Significance
Increased screening will identify those with HIV, allowing them to enter care and treatment early, thus improving their health while reducing their infectiousness and (hopefully) their risk behaviors. Opt-out testing is a streamlined process that allows routine HIV testing to become routine.
Design
Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. Information on HIV cases was reported to the CDC through June 2007. Incidence of HIV in the 22 states during 2006 was estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS incidence from 50 states and the District of Columbia.
Main Results
In 2006, an estimated 39,400 people were diagnosed with HIV infection in the 22 reporting states. Of the 6,864 HIV-infected patients tested with the BED assay, 31% were classified as recent infections. Extrapolating these data to the nation as a whole resulted in a new annual HIV incidence of 56,300 (95% CI, 48,200-64,500). This is a 40% increase from the previous estimates.
Significance
The revised HIV incidence data paint a vivid and detailed picture of the epidemic in the United States and likely present a more accurate estimate of how many people acquire the virus.
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
Addition of etravirine led to greater rates of virologic response over 96 weeks, but also reduced progression to an AIDS-defining condition or death -- less than 6% of the etravirine-assigned participants developing these clinical endpoints, compared to about 10% of the patients who were randomized to placebo (P = .04). Furthermore, over the first year of the trial, etravirine-receiving participants had almost 1,000 fewer days of hospitalization than the control participants (1,702 vs. 2,747 days, P = .0195).
Significance
Demonstrate an actual clinical benefit beyond improvements in CD4+ cell count and viral load. Fewer people got sick and died if they received the active study agents. Testament to the ability of these medications, in combination with others, to reverse the ravages of HIV disease. Also indicate that such therapies are best applied before they become too little, too late.
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
Treatment with raltegravir tended to reduce the rate of the development of an AIDS-defining condition or death by about half.
Significance
Demonstrate an actual clinical benefit beyond improvements in CD4+ cell count and viral load. Fewer people got sick and died if they received the active study agents. Testament to the ability of these medications, in combination with others, to reverse the ravages of HIV disease. Also indicate that such therapies are best applied before they become too little, too late.
Design
Population-based study between October 1, 1996 and March 21, 2008.
Population
A total of 8,525 HIV-infected and 2,208,792 HIV-uninfected patients with at least one inpatient or outpatient encounter.
Main Results
Among the patients with HIV infection, the prevalence of fractures of the wrist, hip and vertebrae was 2.87 patients per 100 persons compared with 1.77 per 100 HIV-uninfected persons (P < .0001). The risk of fracture was greater for HIV-infected patients regardless of gender.
Significance
BMD, like so many parts of our bodies, drops as we age. An accumulation of data points toward a heightened risk of significant osteopenia and osteoporosis over time for people living with HIV infection. Shows need for comprehensive approach to the prevention and management of reduced BMD among HIV-infected patients.
Design
Randomized substudy of SMART cohort designed to determine whether a strategy of limiting patients' exposure to antiretrovirals would reduce adverse events such as CVD, hepatic, renal and other complications associated with HIV therapies.
Population
275 substudy participants, 214 had follow-up BMD determinations (116 in the intermittent antiretroviral therapy arm and 98 in the continuous therapy arm). Also examined the rate of fractures in the entire SMART trial cohort of 5,472 participants (providing for approximately 7,500 person-years of follow-up per group).
Main Results
BMD declined in both SMART study groups. However, those randomized to defer or interrupt HIV therapy experienced less of a drop than those who maintained antiretroviral treatment. The estimated differences in mean BMD change from baseline through follow-up were 1.4% (P = .002) at the hip by DEXA, 2.9% (P = .01) for spine by qCT and 1.2% (P = .05) for spine by DEXA -- all favoring drug interruption/deferral.
Significance
Beyond the risk of low BMD that accompanies aging and the lifestyle factors that are more common in HIV-infected patients, the results suggest HIV therapies also kick bone density down the hill. Suggests that our surveillance for BMD problems should be stepped up for those on HIV therapy. The mechanism for such an effect is not known and additional information from this study is likely forthcoming.