Table of Contents
|David Wohl, M.D.|
In the world of HIV/AIDS, no major developments could truly qualify as a breakthrough. Indeed, most of the important advances reported during the past year were leftovers from 2008.
Changes to the HIV/AIDS treatment guidelines1 are always newsworthy and this year the U.S. Department of Health and Human Services (DHHS) panel recommendations contained a few surprises. However, these were overshadowed by the effects of the economic downturn on people living with HIV, which included:
Against this dismal financial backdrop, our political leaders finally busied themselves with repairing our broken and expensive health care system. But in doing so, they have laid bare their pitifully political souls and shown themselves to be indentured to special interests. Tragically, their intransigence and bitter partisanship, as well as a public all too easily confused silly by spin to see how much in need we are of a health care fix, have left reform on life support.
Detailed below are these and other major HIV/AIDS-related stories of 2009. A fitting title for the events of the past year would be "HIV in the Time of the Great Recession." It's not pretty, but neither was 2009.
A review of:
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Panel on Antiretroviral Guidelines for Adults and Adolescents. U.S. Dept of Health and Human Services; December 1, 2009; 1-161.
In medicine, as in stand-up comedy, skeet shooting and love, timing is everything. Yet, when it comes to choosing when to initiate antiretroviral therapy, those of us providing HIV care can be accused of missing a beat. Years ago, when there were only a few modestly active HIV drugs in existence, we prescribed them to HIV-infected people with high CD4+ cell counts -- and the results were lackluster.
Then, when we reserved therapy for those with more advanced disease and an AIDS diagnosis, potent antiretroviral combinations became available and quickly proved to be capable of a miraculous restoration of health -- even among those with less advanced disease. More recently, we have hewed to a 350 cells/mm3 middle path, ostensibly based more on compromise than on science.
However, over the past year, we have seen this threshold attacked on a number of fronts, resulting in a new recommendation by the DHHS HIV treatment guidelines panel that HIV therapy be started at CD4+ cell counts of 500 cells/mm3 or less.1
Spurring the earlier-therapy-is-better charge have been the findings from the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design), an observational cohort study of HIV-infected individuals in the U.S. and Canada. Originally presented in 2008 and instantly achieving "Hottest Abstract of the Year" status, the full report of the results -- fascinating as they are provocative -- was published this year in the New England Journal of Medicine.2 Among over 9,000 patients entering care with a CD4+ cell count greater than 500 cells/mm3, those who delayed starting HIV therapy suffered a significantly greater risk of dying than those who elected to initiate therapy right away. Similar findings emerged when examining more than 8,000 patients with an initial CD4+ cell count over 350 cells/mm3. Mortality data are available for only a subset of the participants. The leading causes of death, as expected, were not clearly HIV-related (e.g., non-AIDS-defining cancers and hepatic, renal and cardiovascular diseases).
Important criticisms have been made of the study. In particular, there is concern for potential unmeasured confounding -- that is, the presence of unappreciated factors associated with a delay in therapy that could also be linked to the risk of death. Further, the analyses of the study are complex and generally above the head of many HIV clinicians for whom complex statistics have been known to induce vertigo, itchy feet and a profound sense of worthlessness. My suspicion is that there are about five people on the planet who truly "get" this study and the rest of us are at their mercy (hey, is that John Grisham in the back of the room taking notes?).
But NA-ACCORD is one note, albeit a loud one, in a chorus of data pointing to moving up the CD4+ cell count starting line. Another observational study, the ART (antiretroviral therapy) Cohort Collaboration, also found higher rates of AIDS and death among a cohort of mostly Europeans who deferred HIV therapy until a CD4+ cell count of 251 to 350 cells/mm3 compared to those who initiated therapy in the range of 351 to 450 cells/mm3.3
However, no significant benefit was detected among those starting therapy above this level, although the ability to see benefits from therapy at high CD4+ cell counts was limited because the cohort had relatively few patients with CD4+ cell counts greater than 450 cells/mm3. Still, as in NA-ACCORD, this study shows that, overall, better outcomes can be expected with earlier therapy.
Because observational data can be influenced by unseen forces, they always need to be interpreted with some caution. Randomized trials -- although not completely immune from bias -- are preferable. At present, there are no results from randomized studies assigning patients to start or defer therapy at counts greater than 350 cells/mm3.
However, there is just such a trial currently enrolling patients. START (Strategic Timing of AntiRetroviral Treatment) is being conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). They are randomizing patients with CD4+ cell counts greater than 500 cells/mm3 to therapy versus treatment deferral until counts hit 350 cells/mm3 or less. Neat idea, but there are worries regarding the ability of the study to enroll and that even if full accrual is achieved, it will be several years before the results of this study become available.
There was, however, a randomized study of over 800 HIV-infected patients with CD4+ cell counts between 200 and 350 cells/mm3 (median = 280 cells/mm3) conducted in Haiti. The study randomized participants to either immediately initiate HIV therapy with zidovudine (AZT, Retrovir), lamivudine (3TC, Epivir) and efavirenz (Sustiva, Stocrin) or delay treatment until their CD4+ cell count dropped below 200 cells/mm3 or if clinically indicated.4
As with so many landmark studies, the trial was stopped early when it became evident that the immediate treatment arm enjoyed significantly better survival rates, as well as reduced rates of tuberculosis -- a major opportunistic infection in Haiti -- compared to the treatment deferral arm.
Playing a supporting role alongside the observational data are studies that link HIV-induced immune activation and inflammation to adverse outcomes and their surrogates, as well as studies showing an association between CD4+ cell depletion and malignancies and cardiovascular disease.5-10 These studies have helped create a growing awareness of the potentially deleterious effects of uncontrolled HIV -- a powerful counterweight to concerns regarding antiretroviral toxicity -- that has tipped the scales back in favor of earlier initiation of therapy. HIV therapy may have its adverse effects, but the toxicity of HIV itself, even at high CD4+ cell counts, may very well be worse.
Given this background, what do the DHHS guidelines say exactly? Before attempting to deconstruct the guidelines, one should appreciate two important facts. First, all panel recommendations are rated according to a system that assesses both the strength of the recommendation (A = Strong, B = Moderate, C = Optional) and the quality of the underlying science (I = randomized trial, II = non-randomized or observational data, III = Expert Opinion only). So, a recommendation rated "AI" is one that is strong and based on randomized clinical trial results. Second, to support a recommendation of any strength, at least two thirds of the DHHS panel must agree to it.
For reasons that become clearer when reading the recommendations, understanding these points is important to interpreting the guidelines. The updated recommendations for when to start HIV therapy are:
Therefore, as in the previous version of the guidelines, it is recommended that patients with symptomatic HIV disease, a CD4+ cell count below 350 cells/mm3 and certain conditions start HIV therapy. However, the recommendation to initiate therapy is now extended to those with a CD4+ cell count between 350 and 500 cells/mm3.
The panel was almost evenly divided regarding whether the strength of this recommendation should be A or B, but not on the recommendation itself. In contrast, the revision makes it clear that the panel was absolutely divided when it came to treating those with a CD4+ cell count greater than 500 cells/mm3.
Moving the treatment initiation threshold to 500 cells/mm3 was a bold move for the DHHS panel and coming as it did on Dec. 1, 2009, there has been limited time to assess the reactions among the HIV community to this revision.
Many clinicians who had seen the data in real time and are appreciative of the convenience and tolerability of our current first-line regimens had already been dialing up the CD4 start number and for them the updated recommendations barely elicited a yawn.
Similarly, many patients who were diagnosed at relatively high CD4+ cell counts often question the logic of permitting declines in their CD4+ cell counts to abnormally low levels.
In contrast, the more cautious are likely to object to the changes, particularly the notion of treating those with CD4+ cell counts exceeding 500 cells/mm3, on the grounds that there is a lack of sufficient evidence of benefit and an absence of data on longer term adverse complications.
In transparently displaying its own desynchronized take on where the HIV treatment sweet spot sits, the guidelines panel reflects our own love-hate relationship with antiretrovirals. The power of these medications is unquestionable and they have saved untold lives, but we have been ambushed by the toxicity of earlier antiretrovirals and it is understandable if we are reluctant to leap before we very carefully look.
For those looking to the guidelines as some sort of decalogue that will provide precise instructions on what to do, this section of the guidelines will be a letdown (even worse, the text almost begs the reader to actually read the stuff written below the big boxed bolded bullet points!).
Instead, this is a document that guides the practitioner through the terra firma of conclusive data and into the less secure territory where extrapolation and inference mark the way. It is there, where equipoise lives and the experts point in opposite directions, that clinicians have to make a decision. But I recommend you first read the text.
A review of:
Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Reuben M. Granich, Charles F. Gilks, Christopher Dye, Kevin M. De Cock, Brian G. Williams. The Lancet. January 3, 2009;373(9657):48-57.
It was in 2009 that I first encountered the term "Test and Treat," also known as TNT. Actually, what I initially heard was someone discussing the importance of TNT in HIV prevention and I thought I had missed out on a new microbicide with a dynamite name.
As many people are now aware, the idea behind TNT is to find people with HIV and prescribe HIV treatment in order to render them less infectious and thus prevent transmission of the virus to others.
Everyone agrees that too many men and women are unknowingly HIV infected and finding these people must be a public health priority. Treatment, maybe even at high CD4+ cell counts (see top story number 1), maintains or restores health and also reduces HIV levels in the fluids we share with others -- which has to be a good thing.
Reuben Granich et al. IAS 2009; abstract MOPL101. Reprinted with permission. Click here to view the full presentation.
The diagnosis of HIV infection also provides opportunities for HIV prevention counseling using evidence-based interventions.
So, how well can TNT work? In a thought-provoking paper published in the Lancet, a team from the World Health Organization (WHO) created hypothetical models to answer this question.11 Using as an example South Africa -- a country that is home to 17% of the HIV-infected people on our planet and where HIV transmission has been considered to be almost exclusively heterosexual (although, it is becoming clearer that men do have sex with men in southern Africa) -- the models examine the timing of HIV treatment as well as various testing and treatment strategies for the potential for eliminating HIV. You read that correctly, eliminate HIV, where elimination is defined as an incidence of less than 1 case per 1,000 population per year.
All such models have assumptions and here there are many. Foremost, the authors assume that every man and woman age 15 years and older in a population can be screened for HIV annually and then treated immediately regardless of CD4+ cell count at diagnosis.
They base treatment uptake and response on data from Malawi and use other data to support additional assumptions such as the expected transmissibility of HIV at different stages of infection and an anticipated drop in infectiousness with HIV therapy to just 1% of that pretreatment.
Under such a theoretical program of annual HIV testing, coupled with the initiation of immediate antiretroviral treatment in all those detected, in a population like that found in South Africa, the elimination of HIV transmission may be able to be achieved by 2016. It is also estimated that before the middle of the century, the overall prevalence of HIV infection would be reduced to less than 1%, with HIV-related deaths cut in half.
Wow. Even better, such a strategy, despite heavy up-front costs, would save money in the long run, according to the cost-benefit analyses conducted by the researchers. No wonder this paper has generated much discussion and even prompted the leadership of the National Institute of Allergy and Infectious Diseases (NIAID) to draft a framework for future research into the major tenets and obstacles to TNT.12
Such modeling is fascinating to read and, like science fiction, it frees the mind to imagine what could be. But unlike fantasy, such models attempt to emulate reality.
Clearly, in this exercise, it is acknowledged that some of the assumptions that make it work are grandiose. Universal testing is -- from a purely logistical perspective -- almost impossible in non-totalitarian nation states. Likewise, the expectations regarding the patient response to HIV treatment -- based on data from patients with more advanced disease -- and the effect of therapy on transmission seem a bit Pollyannaish.
The model should not be taken too literally as a prescription for the end of AIDS as we know it, but instead should be seen as a starting point to reassess how we can contain the spread of HIV.
The strategy's obstacles and limitations are some of the same we need to confront in reining in the HIV epidemic. Their approach may defensibly be accused of being radical, but with an effective HIV vaccine not likely in the near term and the success of microbicides thus far limited, perhaps extreme action is what it will take to actually eliminate HIV in real life. The tools we have available to us are the biological, in the form of antiretrovirals, and the behavioral. Are we using these tools to their fullest?
As discussed above, current antiretroviral use has been reserved for patients with evidence of at least moderate immunosuppression. During the treatment-free period, secondary transmission of HIV occurs. Available data -- including observational studies of serodiscordant couples and the demonstration of reductions in HIV concentrations in the genital secretions of men and women treated with certain antiretrovirals -- support the concept of treatment as prevention.13-16
However, extending the use of antiretrovirals beyond the benefit of the individual to the benefit of the health of the partners of HIV-infected individuals requires an extension of our own thinking about HIV therapy. Some researchers fear this may come at a cost. Drs. Geoffrey Garnett and Rebecca Baggaley, epidemiologists at the Imperial College London, argue in an editorial accompanying the paper that, "At its worst, the strategy will involve over-testing, over-treatment, side-effects, resistance, and potentially reduced autonomy of the individual in their choices of care."17 They further caution that shifting the benefits of HIV therapy from individual to public health can lead us down a slippery slope of enforced testing for the "public good." On the other hand, if the TNT strategy is only partially successful in seeking people to be tested, HIV could become concentrated in pockets of hard to reach and very high-risk individuals, vulnerable to stigmatization and coercive policies.
From a practical standpoint, we do not know if TNT will work. A different computer model, simulating the effect of TNT on the HIV epidemic in Washington, D.C., where 3% of adults are HIV infected, found that this strategy would have a limited impact on HIV transmission.18
In the Washington, D.C., study, one exercise assumed 80% of the population would be offered HIV testing, of whom 60% would accept the test. Among the people who tested positive for HIV, 80% would be expected to link successfully to HIV care and treatment. Under these conditions, annual HIV screening and immediate antiretroviral therapy at detection would reduce the proportion of the time HIV-infected individuals would have detectable HIV-RNA levels (> 500 copies/mL) from 65% with the current testing strategy to 44%. But this strategy would produce little change in the absolute number of infectious people over the first 18 months following implementation. Even 100% testing of the population was found to have only a transient effect on the number of viremic individuals in this model.
All the answers are still not known and rather than take a faith-based approach to TNT, additional investigation of the major elements of this approach are needed. The trick is to figure out how best to do this given the nature of the intervention (mass HIV testing and treatment) and the outcomes of interest (community viral load and HIV incidence).
Demonstration projects of TNT are underway and creative types are busily devising responses to the NIAID call to test TNT in the real world. Simply envisioning an end to the HIV pandemic with modeling is thrilling, but at some point it will be time to shut off the computer and go outside and prevent.