Annotated Abstracts of Journal Articles
2015, 3rd Quarter
Annotations by Oliver Freudenreich, MD, FAPM and Mary Ann Cohen, MD, FAPM
September 2015
Also of interest:
The Americans with Disability Act was enacted 25 years ago. This article describes how the treatment of HIV/AIDS care has changed for the better, but also how many unresolved issues remain in the U.S. that lead to not diagnosing HIV early, and to the tragedy of inadequate retention in care leading to the lack of full viral suppression.
While overt discrimination in the work place is made more difficult with legal protection in place, stigma is alive and well for many groups like LGBT people who will need better civil rights protection, or as reflected in states that keep criminalization of non-disclosure laws on the books. Unfinished business remains with regards to truly covering every person for HIV-related services including screening, despite the Affordable Care Act. The article calls for creating an optimal social and legal environment so that everybody can live freely and access health care where needed, without having to fear stigma and discrimination.
First released by President Obama in 2010, the National HIV/AIDS Strategy is a five-year plan that details principles, priorities, and actions as well as measurable goals to guide the domestic response to the HIV epidemic. This Update for the next 5 years incorporates new scientific findings and progress made to achieve the strategic vision (“The United States will become a place where new HIV infections are rare and when they do occur, every person regardless of age, gender, race/ethnicity, sexual orientation, gender identity or socio-economic circumstance, will have unfettered access to high quality, life-extending care, free from stigma and discrimination.”). Perusing the 10 indicators of progress (e.g., “Increase the percentage of persons with diagnosed HIV infection who are virally suppressed to at least 80 percent.”) provides an excellent blueprint for the next 5 years.
Volk JE, Marcus JL, Phengrasamy T, et al
Clin Infect Dis 2015; pii: civ778 [Epub ahead of print]
ANNOTATION (Freudenreich & Cohen)
The Finding: This observational cohort study of 657 (mostly) gay men in San Francisco who received their care from Kaiser Permanente found that none of them contracted HIV over a 2-year study period after they started PrEP because of their high-risk status. The mean duration of PrEP use was 7.2 months. 40% of patients reported that their condom use had decreased. After starting PrEP, half of them became infected with syphilis, gonorrhea, or chlamydia within a year.
Strength and Weaknesses: This was a large trial (amounting to 388 person-years of observation) in one important patient group (i.e., gay men who have sex with men); other risk groups were not represented. This study was able to engage patients via a specialized program in a primary care setting; it is unclear if other settings would be equally successful. Drug levels were not collected but the results suggest that patients were adherent (they were motivated to begin with and asked their clinician for PrEP). This being an observational study, causation cannot be established regarding the increase in non-HIV STDs as a result of starting PrEP.
Relevance: PrEP was approved by the FDA in 2012 but most of the evidence for its efficacy comes from randomized clinical trials. This study from a real-world clinical setting adds to the evidence that PrEP is a highly effective strategy to prevent new HIV infections in patients with high-risk behaviors. This is very encouraging. However, condom use decreased, and non-HIV infections increased over the observation period, which suggests ongoing clinical screening is needed in this high-risk group. As opposed to HIV, such STDs are highly treatable and a risk-benefit analysis would thus still favour PrEP.
Referrals for and initiation of preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection increased dramatically in a large clinical practice setting since 2012. Despite high rates of sexually transmitted infections among PrEP users and reported decreases in condom use in a subset, there were no new HIV infections in this population.
INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al
N Engl J Med 2015; 373(9):795-807
ANNOTATION (Freudenreich & Cohen)
The Finding: A multi-site (multi-continent) trial randomized 4685 patients who had a CD4 count above 500 to either receive HAART immediately or defer treatment until the CD4 count had declined to below 350, which is a treatment threshold recommended by many guidelines. The primary composite end point (one of three: any serious AIDS-related event, serious non-AIDS-related event, or death from any cause) occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years) which was significant [hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001)].
Strength and Weaknesses: This was a large clinical trial that was conducted world-wide and is therefore representative for most clinical settings. The composite primary end point included clinically meaningful events. While this trial answered the study questions (it was in fact terminated early), the overall number of 138 primary end-point events was small to allow for examining the effects of treatment decisions on individual diseases. The study duration of 3 years is also too short to detect long-term sequelae of HAART use.
Relevance: This is a milestone publication in the history of the treatment for HIV/AIDS as it settles the question (at least for now) of when to start HAART: unless there are specific clinical reasons or patient preferences, starting HAART at the time of diagnosis regardless of CD4 count can be confidently recommended if one wants to reduce clinically relevant events related and unrelated to HIV/AIDS; treating immediately probably improves the immune status more compared to waiting. That said, the absolute risk for any such event is low in patients with CD4 counts above 350 or 500, and some patients might thus prefer to delay treatment; tolerability and long-term toxicities of HAART remain clinical concerns that patients and clinicians need to factor in. It must also be clearly noted that the (dys-)function of the immune system is not fully captured by the CD4 count, and complications from being infected with HIV can occur even at seemingly safe CD4 counts.
Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.
Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.
Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.
Conclusions:The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.
(Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).
