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Clinical Management
Clinical ManagementThe Body PRO
February 2007
Table of Contents
- Introduction
- Top 10 Medical Stories of 2006:
- The SMART Study -- A Treatment Interruption Trial
CD4+ count-guided interruption of antiretroviral treatment
By the Strategies for Management of Antiretroviral Therapy (SMART) Study Group, et al, The New England Journal of Medicine, November 30, 2006 - ACTG 5142 -- Battle of the Titans
A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection -- ACTG 5142
By SA Riddler, et al, XVI International AIDS Conference, August 13-18, 2006 - A Trio of Other Comparative HIV Treatment Trials: KLEAN, BMS-089 and Gilead 934
The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial
By J Eron Jr, et al, The Lancet, August 5, 2006
and
Efficacy and safety of atazanavir-based therapy in antiretroviral naive HIV-1 infected subjects, both with and without ritonavir: 48-week results from AI424-089
By N Malan, et al, 13th Conference on Retroviruses and Opportunistic Infections, February 5-8, 2006
and
Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV
By JE Gallant, et al, The New England Journal of Medicine, January 19, 2006 - Randomized, Controlled Studies of Male Circumcision to Prevent HIV Acquisition
Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 trial
By B Auvert, et al, PLoS Medicine, November 2005
and
Circumcision and HIV transmission
By TC Quinn, Current Opinion in Infectious Diseases, February 2007 - The Benefits of HIV Treatment and the Price Tag
The lifetime cost of current human immunodeficiency virus care in the United States
By BR Schackman, et al, Medical Care, November 2006 - Value of HIV Viral Load in Predicting CD4+ Cell Count Decline
Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection
By B Rodríguez, et al, The Journal of the American Medical Association, September 27, 2006 - My Big Fat Metabolic Study: ACTG A5005s
DEXA outcomes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz or both plus dual nucleosides: long-term results from A5005s, a substudy of ACTG 384
By M Dubé, et al, XVI International AIDS Conference, August 13-18, 2006 - Brave, New CDC HIV Testing Recommendations
Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings
By BM Branson, et al, Morbidity and Mortality Weekly Report Recommendations and Reports, September 22, 2006 - Updated U.S. DHHS Guidelines for the Initial Treatment of HIV Infection
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents
By the Panel on Clinical Practices for Treatment of HIV Infection, October 10, 2006 - The Next HIV Therapies
Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients
By M Markowitz, et al, XVI International AIDS Conference, August 13-18, 2006
and
Potent efficacy of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data
By B Grinsztejn, et al, 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27-30, 2006
and
Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223
By C Cohen, et al, XVI International AIDS Conference, August 13-18, 2006
and
Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in Study TMC125-C227
By B Woodfall, et al, 8th International Congress on Drug Therapy in HIV Infection, November 12-16, 2006
and
Safety and efficacy of MARAVIROC, a novel CCR5 antagonist, when used in combination with optimized background therapy for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial
By H Mayer, et al, XVI International AIDS Conference, August 13-18, 2006
- The SMART Study -- A Treatment Interruption Trial
- Runners Up
- References
Introduction
In the world of HIV research, 2006 was the year of the head-to-head HIV clinical trial. Well-powered, randomized, controlled, comparative studies tend to be large, expensive and lengthy -- and, as a result, they have a hard time keeping pace with the rapidly evolving field of HIV clinical management. It takes years to go from the initial conceptualization of a study to the release of final results; thus, what at first made for an intriguing research question, frequently ends up becoming mundane -- or worse, irrelevant. Like the light from a distant star, the results of these period-piece trials often come to us long after the drugs under study have seen their market share go supernova.
However, last year, several well-designed, comparative studies were either presented or published that answered questions relevant to today's clinical practice. In several cases, the studies were conducted quickly and were prescient in their design (i.e., ACTG 5142). In more than one case, the relevance is due to the fact that the studies' findings were not at all what the investigators expected (i.e., the SMART study, ACTG 5142 and A5005s).
To a clinical trialist such as myself, this glut of topical research is just way too cool. I found 2006 to be a refreshing and reaffirming 12 months. Refreshing in that we had some excellent comparative studies that broke a stalemate among researchers and clinicians regarding an important clinical issue; reaffirming because some of these studies, with their well-considered design and impressive execution, reminded me of the reason I went into this field.
We design clinical studies to fill gaps in our knowledge, so we can learn how to better care for our patients. Ideally, the motivation for the study is a disagreement among researchers and clinicians as to the answer to a specific clinical question; some hold firmly that the result will lie in one direction, while their learned colleagues shout back that, on the contrary, it will point the other way. To find out the answer, we experiment. This year, our experiments yielded many important answers.
The trials of 2006 that I felt had the greatest immediate or potential impact on how we approach treating people affected by the HIV epidemic are included in the major HIV medical stories of 2006 listed below. Most are clinical treatment studies; others are not, but all, I think, still challenge us to reconsider how we practice HIV care and how we can prevent further expansion of the HIV epidemic. All are worth reading and appreciating.
The SMART Study -- A Treatment Interruption Trial
A review of:
CD4+ count-guided interruption of antiretroviral treatment. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, WM El-Sadr, JD Lundgren, JD Neaton, F Gordin, D Abrams, RC Arduino, A Babiker, W Burman, N Clumeck, CJ Cohen, D Cohn, D Cooper, J Darbyshire, S Emery, G Fatkenheuer, B Gazzard, B Grund, J Hoy, K Klingman, M Losso, N Markowitz, J Neuhaus, A Phillips, C Rappoport. The New England Journal of Medicine. November 30, 2006;355(22):2283-2296.
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The study they designed was straightforward. HIV-infected individuals with a CD4+ cell count greater than 350 cells/µL were randomized to continuous antiretroviral therapy based on U.S. Department of Health and Human Services (DHHS) treatment guidelines2 (the viral suppression arm) versus episodic antiretroviral therapy based on CD4+ cell count (the drug conservation arm), in which therapy was discontinued after the CD4+ cell count rose to 350 cells/µL or greater and then reinitiated when the CD4+ cell count fell below 250 cells/µL.
Participants were eligible for the trial regardless of antiretroviral treatment experience; however, less than 5% of the cohort was treatment naive. As described in an editorial in the New England Journal of Medicine by Judith Currier and Lindsey Baden3 that accompanied the paper's publication, at the time the study was designed, there was considerable concern in some quarters of the scientific community regarding the wisdom of interrupting effective HIV therapy. However, there was also a counterbalancing intense interest among clinicians, as well as patients, in strategies to reduce antiretroviral-related adverse effects and treatment fatigue.
The study, which was initiated by the U.S. National Institutes of Health (NIH)-funded Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), opened in early 2002 in 33 countries and eventually enrolled 5,472 participants. Over 80% of the participants lived in North America or Europe; the median CD4+ cell count was 597 cells/µL and 72% had a plasma HIV RNA level less than 400 copies/mL. The trial had been expected to run until at least an average of six years of participant follow-up had been achieved. However, the trial was abruptly halted by the study's Data and Safety Monitoring Board (DSMB) with a mean on-study follow-up time of only 16 months.
What happened has become the most recent entry into the "Annals of Completely Unanticipated Study Results." Rather than protect patients, the withdrawal of HIV therapy increased the risk of death from any cause, including that of opportunistic infections. In addition, the rates of cardiovascular, hepatic and renal disease -- which are often considered antiretroviral-related -- were greater in the treatment interruption group (see Table 1).
Click to enlarge
Adapted from Wafaa El-Sadr, M.D., M.P.H., et al. N Engl J Med. 2006;355(22):2283-2296.
An explanation of these results, which the investigators admit were "surprising," centers on the profound worsening of immunodeficiency observed in the drug conservation arm. CD4+ cell counts dropped by an average of 87 cells/µL per month over the first two months in this group after treatment discontinuation and then continued to decline steadily.
During study follow-up, the CD4+ cell count was an average of 206 cells/µL lower in the drug conservation arm than in the viral suppression arm. Not unexpectedly, the proportion of participants with virologic suppression plummeted with treatment cessation in the drug conservation arm, falling from 72% to 6% during the first two months of study participation.
Adjustment for the latest on-study CD4+ cell count and viral load reduced the hazard ratio for mortality classified as not related to AIDS-associated opportunistic conditions in the drug conservation group compared to the viral suppression group, implying that immunosuppression and uncontrolled viremia provide at least a partial explanation for the differences between the study groups.
According to data presented at the XVI International AIDS Conference (AIDS 2006) in Toronto, Canada, this past summer by the SMART investigators, the superiority of the viral suppression strategy was observed in all subgroups of participants that were analyzed.4,5 While the greatest risk for opportunistic disease or death was, as expected, observed among patients who had CD4+ cell counts of less than 350 cells/µL, continuous HIV therapy was found to be more beneficial than treatment interruption even among those participants with CD4+ cell counts that remained above 350 cells/µL and who, therefore, would be considered at less risk for adverse outcomes.
These analyses also demonstrate that, in fact, patients who had higher CD4+ cell counts and suppressed viral loads experienced particularly worse outcomes during their treatment interruptions. Thus it turned out that patients who were doing well on their antiretroviral therapy had more to lose from stopping therapy than those who were receiving relatively less benefit from their HIV treatment due to non-adherence (i.e., self-directed treatment interruptions) or other factors.
The Bottom Line
This CD4+ cell count-directed-intermittent HIV treatment interruption was found to be hazardous across the board. Patients who may seem most attractive for such a break -- such as those who have higher CD4+ cell counts and lower viral loads -- were most likely to experience an adverse event compared to patients who remained on therapy.
The findings of this trial are significant on several levels. First, the inferiority of the drug conservation strategy has chilled any notion of structured treatment interruptions. In their editorial, Currier and Baden suggest that long-term treatment interruption may be safe only for people who did not need HIV therapy to begin with (e.g., patients who have extremely high CD4+ cell counts when initiating therapy) and that there remain few circumstances in which a treatment interruption may continue to have a role. This would include interrupting treatment following therapy initiated during acute HIV infection and in women with high CD4+ cell counts who received HIV therapy to prevent HIV transmission during pregnancy, as well as brief interruptions (i.e., a few weeks) due to serious side effects in those with chronic HIV infection.
Some people may argue about the appropriateness of the CD4+ cell count "floor" that the investigators used to trigger resumption of antiretroviral therapy. The investigators felt a CD4+ cell count threshold for reinitiating HIV therapy of 250 cells/µL was safe given historic data demonstrating low rates of disease progression among HIV-infected patients with counts above 200 cells/µL.
Those who disagreed countered that a threshold of 250 cells/µL was cutting things too close. They would have preferred that therapy restart at a higher count. It is likely that any future studies of treatment interruption -- were they to be conducted -- would not tolerate the degree of immunosuppression experienced by participants in the drug conservation arm of this study.
Without a doubt, the superiority of continuous HIV therapy brings us back to the altar of treatment-worship. Concerns over the perceived complications of HIV therapies are giving way to a newfound appreciation for the toxicity of unchecked HIV viremia and progressive CD4+ cell count depletion.
The finding that sustained treatment holidays are largely a bad idea is absolutely clear from the findings of the SMART study. Clinicians must now share these results with their patients, who also need to understand the potential perils of their dabbling in therapy interruptions. Given the popular prejudices regarding HIV therapy, more than a few patients will be surprised to find that survival and cardiovascular outcomes were better in the continuously treated participants of this large study.
The intriguing finding of excess cardiovascular, renal and hepatic disease among patients assigned to the treatment interruption arm adds to an emerging body of evidence suggesting a role for both immunosuppression and HIV viremia in the etiology of some of these conditions. Higher rates of renal, hepatic and neurological adverse effects were also reported in untreated HIV-infected patients compared to those starting therapy in the HIV Outpatients Study (HOPS).6 It is possible that viremia, and its attendant immune activation, may provoke inflammatory reactions that can lead to end-organ damage. The suggestion that HIV therapy may actually be protective against cardiovascular disease will require careful examination within this study, as well as other studies.
Lastly, the trial was a coup for the scientific method and a testament to the value of studies on research questions that many people think they know the answer to in the absence of sufficient data. The investigators' hypothesis (that had been shared by many smart people) was proved to be false. The surprising results have led to a dramatic shift in our thinking about antiretroviral treatment and the complications of HIV and its therapies.
ACTG 5142 -- Battle of the Titans
A review of:
A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection -- ACTG 5142. SA Riddler, R Haubrich, G DiRienzo, L Peeples, WG Powderly, KL Klingman, KW Garren, T George, JF Rooney, B Brizz, D Havlir, JW Mellors, AIDS Clinical Trials Group 5142 Study Team. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0204.
View slides: Download PowerPoint
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Often the ACTG, as a federally funded research network, is uniquely able to conduct comparative trials that the pharmaceutical companies have no interest in performing. Such was the case for ACTG 5142,7 which pitted the two longest-standing, guideline- recommended antiretroviral treatment regimen anchors, efavirenz and lopinavir/ritonavir, against one another.
Naturally, there were the expected ACTG idiosyncrasies. Although independent from the pharmaceutical industry, the ACTG relies on drug companies to provide study medications free of charge. In this case, not everyone from big pharma was eager to play. As a result, for a large proportion of the study participants, not all the HIV medications were supplied at no cost -- leading to an over reliance on extended release stavudine (d4T, Zerit), which was provided gratis to the investigators.
In addition, there are the usual ACTG statistical quirks, such as undetectable being defined as less than 200 copies/mL, composite endpoints and non-traditional P-values. But these probably just indicate that ACTG statisticians are simply smarter than the rest of us.
The design of this trial may be well known to most readers since it snagged a lot of attention this past summer at AIDS 2006, where it was first presented. Efavirenz and lopinavir/ritonavir were compared to each other in combination with a pair of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The NRTIs were chosen by the clinicians and patients, and 753 HIV treatment-naive participants were enrolled.
Importantly, during the initial phase of the study, only one of the NRTI options was provided at no cost to the participant, and this was the extended-release stavudine. Later, tenofovir (TDF, Viread) was also made available by the study at no cost to patients. This led to overuse of stavudine, which is now considered too toxic for use when alternative NRTIs are readily available. A third, "nuke-sparing" study arm consisted of only efavirenz + lopinavir/ritonavir without accompanying NRTIs.
At present, everything we know about the findings of this study was presented at AIDS 2006 during a 15-minute late breaker session by Sharon Riddler of the University of Pittsburgh. Essentially, the study demonstrated that at week 96 a significantly greater proportion of participants who had been assigned to receive efavirenz + two NRTIs reached the virologic endpoints of a plasma HIV RNA level of less than 200 copies/mL or less than 50 copies/mL, compared to participants who had been randomized to receive lopinavir/ritonavir + two NRTIs (Table 2). The nuke-sparing regimen produced results that were, generally, in between those of the other two study arms.
So, round one goes to efavirenz. However, the results included some more surprises. When looking at participants' immunological responses, patients who had been assigned lopinavir/ritonavir were found to have had a (statistically) significantly greater gain in CD4+ cell counts over 96 weeks of treatment (Table 2).
Although limited data were presented on toxicity, those that were shown were tantalizing. In the two NRTI-containing arms, about one third of participants experienced a moderate or severe laboratory abnormality, and approximately 20% had a new high-grade sign or symptom. But, there were no major differences in the rates of these events between these two arms. The nuke-sparing arm did produce a high rate (45%) of moderate or severe laboratory abnormalities. Off-the-chart hypertriglyceridemia was rare in both NRTIs arms (less than 6%), but was high (14%) in the nuke-sparing arm -- perhaps accounting for much of the excess laboratory adverse events seen in this arm. Data on lipid-lowering drug use was not presented.
Additional lipid and body shape data were reserved for presentation at the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007) in Los Angeles, Calif.
Particularly noteworthy was that the time to first treatment-limiting toxicity was observed to be no different among the three study arms at 96 weeks. More than 80% of the participants remained free of such an adverse event.
However, when examining the composite study endpoint of "regimen completion" -- which was defined as virologic failure (lack of viral suppression or rebound) or toxicity requiring discontinuation of any component of the regimen -- at 96 weeks, 56% of the patients who were assigned to lopinavir/ritonavir + two NRTIs, compared to 40% of those randomized to efavirenz + two NRTIs, reached regimen completion (P = .02). The proportion of participants meeting the study endpoint of regimen completion was similar in the nuke-sparing arm and the efavirenz + two NRTIs arm.
Therefore, 50% to 60% of the participants assigned to these state-of-the-art therapies experienced either a virologic failure or an adverse event requiring a change in one or more of their antiretrovirals (note: a quarter of the participants were taking extended-release stavudine).
Granted, the protocol-specified definition of virologic failure was more stringent than what is typically utilized in clinical practice. To what extent patients with low-level viremia were considered treatment failures was not included in Riddler's brief presentation. Likewise, still unreported is whether treatment modification was related to problems with the NRTIs (i.e., stavudine) rather than the protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) under study. The specific reasons for drug discontinuations also remain unreported.
Less surprising were the viral resistance data. No resistance to lopinavir/ritonavir was observed in participants who were assigned to this boosted PI plus two NRTIs. In contrast, resistance to efavirenz was detected in almost half of the patients who failed efavirenz + two NRTIs (however, resistance testing results were not available for everyone). NRTI resistance was observed in more patients with virologic failure while on efavirenz + two NRTIs than in patients in the other two study arms.
The Bottom Line
There was no clear "winner" in this trial, yet it was extremely successful in achieving its goal -- which was to provide clinicians and patients with a side-by-side comparison of two of the most potent and popular antiretrovirals.
Different people will take home differing messages regarding the results according to what is most important to them. For some people, the virologic data will reinforce confidence in efavirenz-based regimens. For others, the resistance and immunologic results will bolster faith in lopinavir/ritonavir and, perhaps by extension, in other boosted PIs.
However, the significance of the results of this trial extends beyond the study aims to compare the efficacy and safety of these regimens. In my view, the beauty of this investigation's conclusions is found in how completely unexpected the results turned out to be. In many of today's HIV clinical treatment trials, the outcome is all but assumed: Powerful drug X is pitted against a known weaker drug Y and, voila!, X wins. Who among you would have predicted that efavirenz would lead to significantly greater rates of viral suppression than lopinavir/ritonavir? And who would have guessed that the rates of high-grade hypertriglyceridemia would be similar between these two drugs? Planned analyses of adverse events and metabolic complications may yield even further surprises. More data from this trial was presented at CROI 2007, and surely a manuscript cannot be far behind.
A Trio of Other Comparative HIV Treatment Trials: KLEAN, BMS-089 and Gilead 934
While no other single trial in 2006 was, in my view, as monumental as either the SMART study or ACTG 5142, there were a few other noteworthy HIV treatment trials, which pitted popular treatment regimens against one another to reveal their relative strengths and weaknesses, that collectively merit inclusion in this list.
A review of:
The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. J Eron Jr, P Yeni, J Gathe Jr, V Estrada, E DeJesus, S Staszewski, P Lackey, C Katlama, B Young, L Yau, D Sutherland-Phillips, P Wannamaker, C Vavro, L Patel, J Yeo, M Shaefer, for the KLEAN study team. The Lancet. August 5, 2006;368(9534):476-482.
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In the industry-sponsored KLEAN trial, the two boosted PIs were compared over 48 weeks in 878 treatment-naive patients at 131 sites across the United States, Canada and Europe. Fosamprenavir was dosed as 700 mg along with 100 mg of ritonavir, both twice a day. Lopinavir/ritonavir in the original soft-gel formulation was also administered twice daily. All study therapy was open-label.
Here again, the results defied the oddsmakers. Across all parameters by which these two regimens were compared -- virologic, immunologic, metabolic -- there were no significant differences between the study arms. There was not even a trend. Both boosted PIs were able to lead to profound reductions in viral load and impressive increases in CD4+ cell count. In the intent-to-treat analysis, in which all those exposed to drug were considered, the rates of viral suppression below 50 copies/mL at 48 weeks were 89% and 88% in the fosamprenavir + ritonavir group and the lopinavir/ritonavir group, respectively (P = NS).
There were no differences in virologic responses by treatment arm when the analysis was stratified by baseline viral load above and below 100,000 copies/mL. The CD4+ cell count increased by a median of 176 cells/µL in the fosamprenavir + ritonavir group (interquartile range [IQR] 106-281) compared to 191 cells/µL in the lopinavir/ritonavir group (IQR 124-287) (P = NS).
Both regimens were also well-tolerated. Only 12% of the patients who were assigned fosamprenavir + ritonavir and 10% of those randomized to lopinavir/ritonavir prematurely discontinued study medication due to adverse events (some of these events were due to abacavir hypersensitivity reactions). The rate of diarrhea, a typical adverse effect with both of these PIs, was similar between the two arms (11% for lopinavir/ritonavir and 13% for fosamprenavir + ritonavir).
Of interest were the lipid data from this trial. There were modest increases in low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting triglyceride levels in both arms but, again, no differences between the two arms with regard to these parameters (Table 4). This is notable as there has been a perception that lopinavir/ritonavir is particularly deleterious when it comes to on-treatment lipid changes and conflicting data regarding the relative effects of these PIs on lipid parameters.
The results from the KLEAN study make it clear that these two boosted PIs are more alike than not, and that the relative merits of one agent compared to the other are not to be found in their ability to reduce viral load, to raise CD4+ cell counts or to even be tolerated during the first year of treatment. This point was well-appreciated by the minders of the U.S. DHHS guidelines who, in their October 2006 update,2 added fosamprenavir + ritonavir at the dose and frequency studied in KLEAN to their list of preferred initial HIV treatment for adults and adolescents (see below).
Atazanavir With and Without Ritonavir -- BMS-089
A review of:
Efficacy and safety of atazanavir-based therapy in antiretroviral naive HIV-1 infected subjects, both with and without ritonavir: 48-week results from AI424-089. N Malan, E Krantz, N David, K Kastango, D Frederick, M Matthew, S Schnittman, J Hammond, and the -089 Study Group. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colo. Abstract 107LB.
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Further, in a comparison with lopinavir/ritonavir in treatment-experienced patients, patients who switched from a failing combination antiretroviral therapy to ritonavir-boosted atazanavir saw a mean reduction in triglyceride, LDL cholesterol and total cholesterol levels.10 In contrast, 48 weeks after the switch, study participants who were assigned to lopinavir/ritonavir experienced an increase in triglycerides and total cholesterol and no change in LDL cholesterol. Although these results demonstrated less of an impact by ritonavir-boosted atazanavir on most lipid parameters in comparison with lopinavir/ritonavir in the treatment-experienced, little information on the effects of boosted atazanavir itself on lipids was provided. The absence of these data made it difficult to appreciate the precise degree to which ritonavir offsets atazanavir's beneficial aspects vis-à-vis lipids, which is exactly what the study known as BMS-089 set out to find out.
BMS-089 was a 96-week, open-label trial of 300 mg of once daily atazanavir boosted with 100 mg of once daily ritonavir versus 400 mg of unboosted atazanavir, both administered with extended release stavudine and lamivudine (3TC, Epivir), in 199 treatment-naive patients. The investigators aimed primarily to examine virologic efficacy, but also were able to detail the lipid effects of atazanavir and ritonavir co-administration.
At 48 weeks, the proportion of participants with a viral load less than 50 copies/mL was not significantly different statistically: 75% in the boosted arm versus 70% in the unboosted arm (95% CI: -7.0, 17.0). However, in the unboosted arm, there were 10 virologic failures compared to only three in the ritonavir-boosted atazanavir arm. Although there were few resistance mutations detected during the study, more people (n = 7) in the unboosted arm were observed to have drug resistance, mostly at the 184 codon. Only one patient in the boosted arm had a resistance mutation (M184V).
Interestingly, there were more adverse effects (mostly related to hyperbilirubinemia/jaundice) in the ritonavir-containing arm compared to the unboosted arm (8% versus less than 1%). Almost a quarter of the participants who were taking ritonavir-boosted atazanavir experienced jaundice compared to 7% in the unboosted-atazanavir group.
In terms of lipids, a ritonavir-effect was evident. Changes in total cholesterol and triglyceride levels were significantly higher in the ritonavir-boosted atazanavir arm (Figure 1).
The significance of these results is reflected in the growing popularity of atazanavir. Clinicians are reaching for this once-a-day PI for a variety of reasons, but the perceptions regarding atazanavir's effects on lipids are a leading rationale for many. This study, albeit hamstrung a bit by the independent lipid effects of extended release stavudine, demonstrates that the addition of ritonavir does increase undesirable lipid parameters, especially triglycerides. Notably, the HDL cholesterol levels also increased, almost identically in both arms.
Virologically, although boosted and unboosted atazanavir both led to similar proportions of patients achieving viral suppression, the study was small. The excess virologic failures and detectable resistance in the unboosted arm indicate a relative lack of potency with regard to this (and probably every) PI when it is not boosted with ritonavir. However, the added virologic potency achieved with ritonavir boosting does come with a price -- beyond the monetary type -- and that is the added risk of significant hyperbilirubinemia and jaundice. As was the case for fosamprenavir, ritonavir-boosted atazanavir was recently added to the U.S. DHHS list of recommended initial therapies.2
Tenofovir + Emtricitabine + Efavirenz Versus Zidovudine/Lamivudine + Efavirenz -- Gilead 934
A review of:
Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. JE Gallant, E DeJesus, JR Arribas, AL Pozniak, B Gazzard, RE Campo, B Lu, D McColl, S Chuck, J Enejosa, JJ Toole, AK Cheng, for the Study 934 Group. The New England Journal of Medicine. January 19, 2006;354(3):251-260.
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The NRTI components of this combination drug have been most rigorously studied in Gilead 934, a head-to-head study of treatment-naive patients randomized to receive open-label tenofovir + emtricitabine (FTC, Emtriva) or fixed-dose zidovudine/lamivudine (AZT/3TC, Combivir) along with their efavirenz. The 48-week results of this study were first published in the New England Journal of Medicine11 and the 96-week data followed in JAIDS.12
After 96 weeks, the proportion of participants with a viral load less than 400 copies/mL (the primary study endpoint) was found to be significantly greater in the tenofovir + emtricitabine arm. However, the proportions of participants within the study arms with viral suppression below 50 copies/mL were not significantly different. These viral endpoints were analyzed using the time-to-loss of viral response (TLOVR), an approach that is preferred by the U.S. Food and Drug Administration (FDA), and that includes treatment discontinuation for virologic reasons as well as for reasons related to toxicity. Therefore, excessive toxicity in one arm could tip the analysis in favor of the other. This was clearly the case at 48 weeks, when higher rates of treatment-limiting adverse effects (largely anemia) in the zidovudine/lamivudine arm led to a significantly greater proportion of participants in the tenofovir + emtricitabine arm achieving the primary endpoint of a viral load below 400 copies/mL. At week 96, this was still the case; however, at this time point there were also significant differences between the arms with regard to the rates of virologic rebound (5% versus less than 1%), which contributed to the superiority of tenofovir + emtricitabine.
Overall, treatment-limiting adverse events were not common, but were more likely with zidovudine/lamivudine (11%) than with tenofovir + emtricitabine (5%) (P = .008). There were no clinical renal events leading to treatment discontinuation in either arm. The median glomerular filtration rate (GFR), estimated by the Cockcroft-Gault equation, declined in both groups over 96 weeks, with no significant difference between the arms seen. However, the Modification of Diet in Renal Disease (MDRD) equation, considered a more sensitive estimate of renal function, did find a greater decline in GFR in the tenofovir + emtricitabine arm. As in other studies of tenofovir, the clinical significance of small, but statistically significant, changes in GFR estimates is unclear.
DEXA (dual energy X-ray absorptiometry) scans were performed at weeks 48 and 96 (but were not performed at baseline!) to assess regional fat. Interestingly, a significant decline (-700 grams) in limb fat was observed in the zidovudine/lamivudine-assigned participants, while patients who were randomized to tenofovir + emtricitabine experienced a median gain (300 grams) in total limb fat. The observation of a drop in limb fat with zidovudine/lamivudine + efavirenz stands in stark contrast to results from ACTG study A5005s,13 a rigorous metabolic substudy of ACTG 384, which found no change in peripheral fat among patients receiving this combination (this study will be examined further later in this paper). In A5005s, DEXA scanning was performed at baseline and at six-month intervals over 144 weeks.
The Bottom Line
These three compare-and-contrast antiretroviral studies provide useful data that clinicians can mull over before reaching for the prescription pad. The unexpected parity of lopinavir and fosamprenavir in the KLEAN study and the performance of atazanavir in BMS-089 suggest that the differences between ritonavir-boosted PIs may not be as vast as we may have once thought.
The 934 study makes it loud and clear that tenofovir + emtricitabine works (duh!) and that it can more than hold its own against zidovudine/lamivudine. The discordance of the DEXA results between the 934 and ACTG studies is interesting and it will take other studies, including A5142, to better address the affect of zidovudine/lamivudine + efavirenz on body fat.
In terms of further qualification of atazanavir, in the future, we can look forward to seeing the results of an ongoing direct comparison of lopinavir/ritonavir and ritonavir-boosted atazanavir in treatment-naive patients.
Randomized, Controlled Studies of Male Circumcision to Prevent HIV Acquisition
A review of:
Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 trial. B Auvert, D Taljaard, E Lagarde, J Sobngwi-Tambekou, R Sitta, A Puren. PLoS Medicine. November 2005;2(11):e298.
and
Circumcision and HIV transmission. TC Quinn. Current Opinion in Infectious Diseases. February 2007;20(1):33-38.
Epidemiologic studies, mostly conducted in sub-Saharan Africa, have overwhelmingly observed an association between male circumcision and protection from infection with several sexually transmitted infections, including HIV.14,15 Even after adjustment for confounding variables, cross-study analyses suggest that circumcised men are approximately 70% less likely to acquire HIV than uncircumcised men.
Given the consistency of the results of these studies, all that was left to clinch this association was a randomized clinical trial. For those of us conducting drug treatment trials, studies that randomize participants to a surgical procedure can seem rather extreme. However, there is a long history of such studies, including recent trials, some even blinded with the use of sham procedures.
Three major randomized controlled studies of male circumcision to prevent HIV infection of men have been initiated in South Africa, Kenya and Uganda. The first of these was published at the end of 200516 and the other two were ended in 2006.17 Each of these three trials was halted when interim analyses demonstrated that medically performed circumcision protected men against HIV infection.
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At that point, there were 20 infections in the intervention group compared to 49 in the control group. This corresponded to a rate ratio of 0.4 (95% CI 0.24, 0.68%; P < .001) -- that is, in this study of South African men, there was a 60% reduced risk of HIV infection with circumcision seen compared to the control group. When these data were analyzed to account for men who were assigned to circumcision and opted out of the procedure and men in the control arm who went and were circumcised on their own during the study, the protective effect was even stronger, at 76%.
The studies conducted in Kenya and Uganda had a similar design to that employed in the South African trial. They too were halted early as a result of the early benefits seen in the circumcision arms. The Kenyan study was conducted in an urban setting and enrolled 2,784 men while the Ugandan trial, based in a more rural region, enrolled 4,996 men.
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The Bottom Line
Even a cynic can appreciate how impressive these results are. Given the difficulty found in motivating behavioral change, there is room for alternative methods to assist in preventing the transmission of HIV and other sexually transmitted diseases that can facilitate HIV acquisition. For sure, there are limitations to the application of circumcision as a global HIV preventative method -- as one international HIV researcher said to me, "We are not going to circumcise ourselves out of the HIV epidemic." This procedure clearly has some finite associated morbidity. And, outside of research settings, the risk of infection and other complications may be higher.
Additionally, the protection afforded by circumcision is hardly absolute; some circumcised men were still infected. While rates of new HIV infection among men undergoing the procedure were lower than those of the control groups, the follow-up time was short due to the halting of these trials. Longer-term study will be needed to understand the durability of the protection circumcision provides.
Further, given the limitations of the protection of circumcision, over time one could imagine a false sense of security among circumcised men that could actually lead to risky behavior and a paradoxical increased exposure to infection.
Additionally, there are few data to indicate whether circumcision will be of much effect in protecting men who have sex with men (MSM). In a study of MSM in the United States, acquisition of HIV was twice as likely in uncircumcised men compared with men who were circumcised.18
That said, in a world where policymakers tell us that the choices for preventing HIV can be summarized by the first three letters of the alphabet, even the limited protection of circumcision is more than welcome.
The Benefits of HIV Treatment and the Price Tag
A review of:
The lifetime cost of current human immunodeficiency virus care in the United States. BR Schackman, KA Gebo, RP Walensky, E Losina, T Muccio, PE Sax, MC Weinstein, GR Seage III, RD Moore, KA Freedberg. Medical Care. November 2006;44(11):990-997.
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Since the beginning of the HIV epidemic, there have been obvious advances in HIV care. This began with the expansion of the antiretroviral armamentarium from one agent to more than 24 agents, spanning at least four drug classes today. In addition, sophisticated tests for the detection and quantification of HIV viremia, as well as drug resistance (and soon co-receptor tropism), have become part of the standard of HIV clinical care in the United States and elsewhere. At the same time, among HIV-infected patients, hospitalization rates have declined, as have serious incapacitating illnesses.19 This has led to prolonged disease-free survival.
To quantify the benefits and costs of HIV medical care in the United States today, Schackman et al created a hypothetical cohort of patients presenting for HIV care. The investigators modeled the characteristics of the patients, their utilization of health services (medication, outpatient and inpatient services and laboratories) and their disease progression. They used data from a number of sources, including the HIV Research Network (HIVRN), a consortium of U.S. HIV clinics, the HIV Cost and Services Utilization Study (HCSUS), the Multicenter AIDS Cohort Study (MACS), U.S. DHHS treatment guidelines, and previously devised models.
Under this model, patients entered care with a mean CD4+ cell count of 310 cells/µL at 39 years of age. The distribution of HIV RNA levels of new patients was based on data from a Boston HIV clinic. Therapy initiation followed the U.S. DHHS guidelines and treatment consisted of a sequence of regimens starting with tenofovir plus one other NRTI and efavirenz and ending with an enfuvirtide (T-20, Fuzeon)-containing salvage regimen. Medication toxicity and virologic failure rates were based on clinical trial data. In all, the investigators aimed to create a realistic model of the U.S. HIV-infected patient population and were inventive in their inclusion of details that could influence care and its costs.
The main result emerging from this simulated model of care was that the projected life expectancy from the time of entry into care for a hypothetical HIV-infected patient was found to be 24.2 years. The total lifetime care cost for a patient who initiated therapy at a CD4+ cell count of less than 350 cells/µL was $385,200 when rebates and other discounts on HIV medications were taken into consideration (the cost increased to $618,900 without such discounts). HAART cost made up 73% of the discounted cost followed by inpatient services (13%), outpatient care (9%) and other HIV-related medication and laboratories (5%). CD4+ cell count influenced cost of care and the sources of the expense. For patients with high CD4+ cell counts, the monthly average cost of care was $2,000 with 77% of this cost due to HIV therapy. In contrast, for patients who had counts less than 50 cells/µL, costs rose to $4,700 per month and inpatient care accounted for 49% of the expense of care.
Analyses were conducted in which the timing of HAART initiation and its effectiveness were looked at. One of the most interesting findings of one of these analyses was that when HAART was initiated when the CD4+ cell count dropped below 200 cells/µL, both cost and survival were reduced, the latter by 1.7 years.
On the other end of the spectrum, if HAART was started at the time of infection, survival jumped to 32.1 years, with a total lifetime cost of only $303,100. The low cost in this case was due to anticipated continued discounting of HIV medications at a rate of 3%.
The Bottom Line
Modeling studies such as this one do what cannot be done with actual human beings. But a model is only as good as the data it is based on and here the investigators -- a dream team of experts in this field -- worked painstakingly to account for everything that may influence cost and care. There are inevitably holes in the virtual reality they created and there are assumptions that may not prove to be true (such as the projected cost of HIV medications). Not included were other costs -- such as those for hepatitis C therapy; mental health and substance abuse treatment; as well as costs for the management of diabetes and cardiovascular disease.
Despite these limitations, these analyses were extremely instructive in that they provided an estimate -- based on all the considerations one can throw into the mix -- of the magnitude of the benefit of HIV therapy and care and, at least, a ballpark figure on the costs. The prognosis aspect of the findings is of great importance to our patients who understandably, want to know what they can expect. This study gives the clinician a reasonable basis from which to answer that toughest of questions.
Value of HIV Viral Load in Predicting CD4+ Cell Count Decline
A review of:
Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. B Rodríguez, AK Sethi, VK Cheruvu, W Mackay, RJ Bosch, M Kitahata, SL Boswell, WC Mathews, DR Bangsberg, J Martin, CC Whalen, S Sieg, S Yadavalli, SG Deeks, MM Lederman. The Journal of the American Medical Association. September 27, 2006;296(12):1498-1506.
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Viral load testing was ushered into clinical practice as a result of data from MACS, an ongoing prospective U.S. study of the natural and treated history of MSM. This cohort demonstrated that higher levels of plasma HIV RNA meant increases in the rate of progression to AIDS or death. Since the publication of these results in 1996,20 they have left an indelible impression on HIV care.
Extrapolating from these results, many clinicians refer to the actuarial-like tables derived from MACS and other cohorts to help patients appreciate the likelihood of disease progression given their CD4+ cell count and viral load. The importance of the pre-treatment plasma HIV RNA level is also reflected in its inclusion in the U.S. DHHS treatment guidelines2 as a parameter to consider when determining the appropriate time to initiate a patient on HIV therapy.
However, there are several observations that have called into question the preeminence of the pre-treatment viral load as a predictor of the rate of CD4+ cell count decline for an individual patient. Foremost, many clinicians have cared for patients who have low viral loads and unexpectedly experience rapid CD4+ cell declines. In addition, there is emerging evidence21 for the role of cell phenotype, co-receptor tropism, immune activation as well as individual HIV-specific immune responses in HIV disease progression.
A study by Benigno Rodríguez et al22 set out to examine the ability of pre-treatment HIV viral load to accurately predict the rate of an individual patient's CD4+ cell count decline. They analyzed data from 1,289 HIV-infected patients culled from several sources, including the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems sites (seven major clinical centers in the United States), the San Francisco Men's Health Study of MSM in that city and the Research in Access to Care for the Homeless (REACH) cohort (a cohort of homeless and marginally housed HIV-infected individuals in the San Francisco area).
All patients included in the analysis were HIV-therapy naive, and it was largely determined that they were not in the throes of acute HIV infection. The investigators were able to collect a contemporaneous viral load and CD4+ cell count and a repeat CD4+ cell count at least six months later, during which time the patients were still not receiving HIV treatment. These data were used to create a model in which a slope of the CD4+ cell count change per individual -- calculated using data from the cohort -- and viral load were included to determine how well the viral load predicted a patient's yearly CD4+ cell count decline.
As has been seen in other cohorts, when patients were grouped into broad categories based on viral load levels, the higher the presenting HIV RNA level strata, the greater the patients' overall subsequent CD4+ cell count decline. Specifically, the median annual-model derived CD4+ cell count decline for those with a viral load of less than 500 copies/mL was 20 cells/µL, for 501 to 2,000 copies/mL it was 39 cells/µL, for 2,001 to 10,000 copies/mL it was 48 cells/µL, for 10,001 to 40,000 copies/mL it was 56 cells/µL and for greater than 40,000 copies/mL it was 78 cells/µL. Therefore, a group of patients with similar viral load levels tends to lose CD4+ cells at a faster rate than a group of patients with a lower level of HIV viremia.
However, the pre-treatment viral load was found not to be an accurate predictor of the speed at which an individual's CD4+ cell count changes. The variability in CD4+ cell count decline between patients was poorly explained by baseline viral load, which indicated that there are other factors with greater influence on the decay of the pool of these cells.
In an attempt to validate these findings, the analysis was repeated -- this time using data from MACS. When this was done, the results were found to be remarkably similar.
To understand how viral load levels can be associated with changes in CD4+ cell count when categorized into broad groups, but not be predictive of the decline of these cells at an individual level, it is helpful to look at Figure 3, in which the distribution of CD4+ cell count changes within each quartile of viral load measured is displayed. There is clearly a wide range of CD4+ cell count changes within each viral load category. In addition, there is marked overlap in the changes in CD4+ cell count across the viral categories. Therefore, while the average CD4+ cell count drop may be steeper in the higher viral load quartile, there are a significant proportion of individuals with similar CD4+ cell count changes in each of these viral load strata.
The Bottom Line
This is an extremely interesting analysis that dramatically challenges the existing belief system regarding the predictive value of quantitative HIV viremia. There are important limitations to Rodríguez et al's study, including the fact that patients who initiated HIV therapy within six months of their initial viral load were excluded from the dataset. In addition, the investigators relied on relatively few viral load determinations to predict CD4+ cell count decline over a fairly short period of time.
However, the rigor with which the investigators attempted to confirm their controversial findings -- reconstructing the analysis using data from the MACS cohort, the very population that was first used by John Mellors and colleagues20 to describe the associations between viral load and HIV disease progression -- makes it difficult to not be impressed by these results and their implications, despite the shortcomings.
Many clinicians have focused on the CD4+ cell count over the viral load when considering treatment initiation. Others, however, take a more aggressive approach and recommend antiretroviral therapy to patients who have high levels of HIV viremia even at relatively high CD4+ cell counts. This study suggests that given the wide variability in CD4+ cell count decline, HIV treatment of such patients cannot be justified as a means to prevent CD4+ cell count depletion.
The study also makes the point that there are other factors besides viremia itself that seem to drive disease progression. In an accompanying editorial,21 Keith Henry, Pablo Tebas and Clifford Lane list several potential influences on the fate of CD4+ cells in HIV-infected individuals and call for the development of therapies that go beyond the targeting of the virus and that enhance immune responses to HIV.
It can be expected that the issue of the predictive value of the viral load will continue to be studied and debated until a consensus is achieved through the replication of study results. Meanwhile, the prudent clinician should perhaps be a bit less dogmatic about what a patient's pre-therapy viral load foretells.
My Big Fat Metabolic Study: ACTG A5005s
A review of:
DEXA outcomes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz or both plus dual nucleosides: long-term results from A5005s, a substudy of ACTG 384. M Dubé, L Komarow, K Mulligan, S Grinspoon, R Parker, G Robbins, P Tebas, the AIDS Clinical Trials Group A5005s and 384 Study Teams. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract WEPE0167.
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The best data we have available regarding body shape during HIV infection come from two studies: the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study23 and the ACTG study A5005s.24 FRAM was a cross-sectional study that clearly demonstrated that fat wasting was the dominant body shape change in the HIV-infected men and women studied. A5005s is a longitudinal substudy of a cohort of patients who are participating in ACTG 384, a trial of six different antiretroviral regimens in treatment-naive participants (Figure 4). The ability of A5005s to rigorously evaluate changes in body shape over time makes it the best source of data regarding these changes currently available.
The initial results of this study were published in 200524 and described changes in fat, as well as lipids and glucose metabolism, over a period of 64 weeks. While much of the attention was drawn to the changes in limb fat, an intriguing finding was that trunk fat measured by DEXA scanning increased in participants who were randomized to either nelfinavir (NFV, Viracept) or efavirenz, regardless of their NRTI assignment. That is, trunk fat increased in all study groups -- those on PI and efavirenz-containing regimens -- with no significant differences in the degree of belly fat gain seen.
In response to this rather unexpected finding, a purist may correctly point out that DEXA scans cannot distinguish subcutaneous (pinch-an-inch) fat from the deep visceral fat that characterizes the increased abdominal girth associated with HIV therapy and that this is a limitation of this study. However, the changes in trunk fat were so similar across all treatment groups, that it is difficult to imagine differential changes in adipose volume in the compartments of the trunk that somehow all balanced out across groups.
During 2006, A5005s produced additional information of major importance for anyone seeking clarity regarding fat and HIV. In an article published in the Journal of Acquired Immune Deficiency Syndromes,25 the A5005s study team found that, during the first 64 weeks of antiretroviral therapy, changes in limb and trunk fat were directionally concordant, with increases in both limb and trunk fat observed in 36% of participants and decreases in both limb and trunk fat detected in 32% of participants. One third of patients had discordant results, and only 26% of the cohort had a decrease in limb fat accompanied by a gain in trunk fat -- the purported sine qua non of the lipodystrophy syndrome.
On top of these data, the investigators presented the 144-week DEXA results at AIDS 2006.26 Importantly, their poster examined the effects of assigning NRTI + NNRTI and NRTI + PI regimens in an "as-treated" analysis, wherein patients who switched assignments were censored from inclusion in subsequent analyses. Previously, the authors had presented data using an intent-to-treat approach, which was less than ideal given the rate of regimen modifications that took place during the study, especially in the stavudine + didanosine (ddI, Videx) arm, which was fairly toxic.
The meat of their presentation is found in the PI versus NNRTI comparison. Participants who were receiving nelfinavir had greater fat loss than those who were receiving efavirenz. Interestingly, there was a 7.9% annual decline in limb fat in the patients who were taking the PI + zidovudine (AZT, Retrovir) + lamivudine, compared to a 2.7% per year gain in the NNRTI group (P = .03). Therefore, patients taking zidovudine + lamivudine + efavirenz did not experience limb fat loss, while those taking these NRTIs with a PI did.
The Bottom Line
These data demonstrate a few things:
- Patients starting HIV therapy overwhelmingly experience changes in their limbs and bellies that are directionally concordant.
- Both PI-based and NNRTI-based regimens are equally associated with increases in trunk fat.
- Limb fat loss was observed with zidovudine + lamivudine only when these NRTIs were administered together with a PI. Limb fat loss did not occur when efavirenz was included.
Regardless, these data should be better appreciated. The finding that trunk fat increases no matter what HIV therapy one starts, provided it works well, is not that much of a surprise as every antiretroviral study that has bothered to look has found likewise (repeat after me, "It is not only PIs that increase belly fat").
The lack of an effect of zidovudine + lamivudine + efavirenz on limb fat is touchier. The industry-sponsored 384 study, discussed above, found that this combination did reduce limb adipose volume. However, as mentioned previously, baseline DEXA scans were not done in that study, so the follow-up time is less and cannot be compared to pre-therapy scans. Again, A5142 provides the best opportunity to examine this combination's effects on regional fat.
Patients are making decisions about therapy based on their perceptions of which therapies are considered most likely to cause metabolic disturbances. At a minimum, they should be advised that fat wasting has become rarer with the U.S. demise of stavudine, and it seems to be even less likely with stavudine-free, NNRTI-based regimens.
Patients should also be told that bigger bellies occur following treatment with both NNRTI-containing and PI-containing regimens. Now that we finally have some clarity on this issue, it is time to plow ahead and discover precisely why some people accumulate visceral fat and others do not and how this complication can be prevented and treated.
Brave, New CDC HIV Testing Recommendations
A review of:
Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. BM Branson, HH Handsfield, MA Lampe, RS Janssen, AW Taylor, SB Lyss, JE Clark. MMWR Recomm Rep. September 22, 2006;55(RR14):1-17.
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Despite the prevalence of this deadly viral infection, screening for HIV has historically targeted people considered to be at "high-risk." Sizing up an individual patient's risk, however, has been a tricky affair for clinicians -- who have been notoriously wanting when it comes to taking sexual histories. It is complicated by the movement of the epidemic to new populations, such as women, who may have relatively few obvious risk factors for infection other than occasionally having sex with a man.29
Clinicians had been previously advised by the CDC to offer HIV testing to only those patients who they considered at risk or more broadly if the prevalence of HIV in the area was 1% or higher.30 The drawback with this suggestion is that most primary care physicians have no ready access to local HIV prevalence data.
As HIV incidence has remained essentially stable over the past years, but has been on the rise in some groups, it has become evident that current screening practices are not working. Following a series of consultative meetings over the last few years, the CDC overhauled its HIV testing recommendations.31 The major revisions include:
- HIV screening is recommended for all patients ages 13 to 64 years. This has been expanded to include all health care settings. Patients need to be notified that testing will be performed and unless the patient declines (opt-out screening) testing will be done.
- Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing.
- Prevention counseling should not be required with HIV diagnostic testing or as part of HIV screening programs in health care settings.
- Persons at high risk for HIV infection should be screened for HIV at least annually.
For pregnant women, the CDC recommends:
- HIV screening should be included in the routine panel of prenatal screening tests for all pregnant women.
- HIV screening is recommended after the patient is notified that testing will be performed, unless the patient declines (opt-out screening).
- Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing.
- Repeat screening in the third trimester is recommended in certain jurisdictions that have elevated rates of HIV infection among pregnant women.
Clearly, attracting the most attention are the recommendations that HIV testing should be offered widely and written informed consent need not be obtained prior to testing. As the epidemic has shifted into a diversity of populations, a significant proportion of HIV-infected persons do not necessarily practice behaviors that could be considered high-risk. Recent studies have described relatively few risk behaviors among some HIV-infected African Americans in the southern United States, especially those who are female.29 Therefore, broad testing will expand testing beyond those who consider themselves, or are deemed by their clinician, to be "at-risk."
The dropping of both the written consent and the extensive counseling prior to HIV testing reflects the experience of clinicians who feel that these procedures are an obstacle to testing.31 Importantly, it must be clear that it is not consent that is eliminated. According to the recommendations, patients still must be informed that they are being tested for HIV and provided an opportunity to opt-out of that testing. But, this information now can be provided verbally.
An additional major departure from prior versions of the CDC recommendations is the suggestion that the results of HIV testing be reported in the same manner as other diagnostic tests. Most clinicians, however, prefer to break the news of HIV infection in person in order to provide emotional support for the patient.
The Bottom Line
Expanding and simplifying HIV testing will surely lead to an increase in testing and is intended to reduce the number of persons unaware of their serostatus. The ultimate goal is to identify people with HIV infection so that appropriate counseling and treatment can be applied to reduce their infectiousness. These bold changes have, not unexpectedly, sparked some controversy.32 Although the potential benefits of expanded and routine HIV testing both to the individual (in terms of detection of HIV earlier in the disease course) and to public health (reduced HIV transmission) have been predicted by published models,33,34 there are concerns that these benefits come at the expense of an individual's autonomy.
Critics point out that HIV continues to be a stigmatizing infection and that the weakening of the consent process heightens the risk of patients being tested without being fully aware of the potential consequences and, in the worst-case, without their consent. There is an additional concern that the increased detection of HIV infection will tax the already overburdened U.S. health care system (including the AIDS Drug Assistance Program [ADAP], which already has capped enrollments and waiting lists in some states35) and lead to increased demand on the limited resources available to care for those currently already known to be infected.
My own view is that we can no longer ignore undetected HIV infection. "Routinizing" HIV testing, I think, is a step toward reducing the stigma associated both with HIV testing as well as being HIV-infected. Certainly, at least some of the people who remain undiagnosed are unintentionally infecting others.
The unwavering incidence of HIV infection in the United States justifies a revamped effort to identify those with chronic and acute HIV and testing is the lynchpin to making headway in reducing HIV transmission. While any resultant surge in HIV diagnoses may increase the short run utilization of care, if these efforts are successful, we will see a reduction in the numbers of persons living with the virus requiring care due to a decline in new HIV cases.
Unfortunately, at present, the CDC recommendations have had limited impact for most clinicians and patients. There are statutory or other regulatory impediments to their implementation, particularly the opt-out screening provision, and these will need to be dealt with before the fruits and/or fouls of the revised recommendations can be seen. But local or regional efforts are being made in emergency rooms and clinics across the country.
Updated U.S. DHHS Guidelines for the Initial Treatment of HIV Infection
A review of:
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Panel on Clinical Practices for Treatment of HIV Infection. U.S. Dept of Health and Human Services; October 10, 2006.
The U.S. DHHS' revised Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents2 are almost always a shoe-in for inclusion on this top 10 list. But this year they take their place on the list because of how boldly they have embraced current HIV care in the United States.
As discussed above, for several years the guidelines have provided a list of preferred first-line HIV regimens that the clinical data best support. This list featured efavirenz and lopinavir/ritonavir as first-line therapy options -- along with certain combinations of NRTIs (zidovudine + lamivudine for either, tenofovir + lamivudine or emtricitabine with efavirenz). And so it remained until this latest update, which sparkles as if it has gone through a makeover on "Queer Eye for the Straight Guy."
Free from the shackles of evidence-based medical literalism, the guidelines cut some slack and recognize that some therapies, even if not yet rigorously tested in randomized, controlled studies against competitors, can produce similar results to the stalwarts of the preferred list. Added to the preferred list was fosamprenavir boosted with ritonavir (700 mg/100 mg twice daily) and atazanavir boosted with ritonavir (300 mg/100 mg). The "column B" NRTI choices have been simplified, appropriately, to either tenofovir/emtricitabine (TDF/FTC, Truvada) or zidovudine/lamivudine.
In addition to revamping the top regimen list, given the high rates of transmitted drug resistance being detected in cohort studies in the United States and Europe,36-38 the guidelines have also strengthened their recommendation that genotypic resistance testing be obtained in patients with chronic HIV infection. There were also cautions included regarding the use of lopinavir/ritonavir as monotherapy -- an experimental approach that has received much attention this past year39-41 -- as well as data regarding the use and adverse effects of the new PIs darunavir (TMC114, Prezista) and tipranavir (TPV, Aptivus).
The Bottom Line
Love them or hate them, they are our guidelines. Now there is more to love. The guidelines, always an excellent source of information on the principles of HIV therapy, have evolved to better reflect how HIV is, and should be, practiced.
The inclusion of fosamprenavir in "column A" of the preferred list is completely justified by the results from the KLEAN study (see above). The addition of ritonavir-boosted atazanavir was a bit more of a leap for the guideline committee. There has not yet been a large head-to-head trial of this boosted PI versus any of the other "column A" agents, although, as mentioned above, the maker of atazanavir is conducting just such a comparative study with lopinavir/ritonavir. Nevertheless, it is clear from BMS-089 (see above) that boosted atazanavir is at least as good as unboosted atazanavir, which was found to be similar to efavirenz in viral efficacy in one large study.42
In short, the U.S. DHHS guidelines are a must-read for anyone caring for HIV-infected patients (at least pages 5 through 28). The tables and figures alone are fantastic. The shot of reality that has been injected into this important document will help the many clinicians who rely on them to guide their care.
Click to enlarge
Adapted from "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents," U.S. Dept of Health and Human Services. 2006.
The Next HIV Therapies
It seems as though there can never be enough HIV medications. For one thing, the prevalence of HIV is increasing -- and there is nothing like expanding markets to motivate product development. In addition, none of the current batches of antiretrovirals have been able to provide long-term viral suppression for HIV-infected patients who live chaotic lives punctuated by periods of suboptimal adherence. As a result, regimens fail patients and patients fail regimens and the need for additional drugs that are more durable and can be active against resistant virus grows.
During the past year, the only new medication approved for the treatment of HIV infection was darunavir, a potent PI that is currently being used in patients with prior antiretroviral experience. In 2007, it is likely that three additional agents will be approved:
- an inhibitor of HIV integrase,
- a new NNRTI with activity against drug-resistant virus and
- the first CCR5 antagonist.
Each of these agents is currently available in the United States through expanded access programs and offers patients with multi-drug resistant virus another chance at controlling their HIV.
MK-0518
A review of:
Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. M Markowitz, B-Y Nguyen, E Gotuzzo, F Mendo, W Ratanasuwan, C Kovacs, J Zhao, L Gilde, R Isaacs, H Teppler, and the Protocol 004 Part II Study Team. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0214.
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and
Potent efficacy of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data. B Grinsztejn, B-Y Nguyen, C Katlama, J Gatell, A Lazzarin, D Vittecoq, C Gonzalez, J Chen, C Harvey, R Isaacs, and Protocol 005 Team. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1670b.
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MK-0518 (known generically now as raltegravir [Isentress]) inhibits HIV integrase, an enzyme that is tasked with the incorporation of viral genetic material into human cellular DNA. There is a long history to the development of inhibitors of HIV integrase. Previous efforts have been plagued by a variety of problems, including toxicity. MK-0518 has distinguished itself both in monotherapy and salvage treatment trials by its potency and tolerability.43,44 In addition, available data45-47 suggest that this agent will have few, if any, interactions with other HIV medications and, as if that was not enough, MK-0518 does not require boosting with ritonavir.
Two major clinical trials of MK-0518 studying treatment-naive and treatment-experienced patients were presented in 2006 and have generated a great deal of excitement.
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In Protocol 004,43 198 treatment-naive patients were administered one of four doses of MK-0518 or efavirenz. All patients also received tenofovir/lamivudine. The mean CD4+ cell count at baseline was approximately 300 cells/µL. At 24 weeks, at least 90% of the participants had a viral load below 50 copies/mL. There were remarkably similar proportions of patients who were treated with MK-0518 or efavirenz with a viral load below 50 copies/mL.
Click to enlarge
Reprinted with permission from Martin Markowitz, M.D., et al.
Impressively, MK-0518 was observed to be extremely active almost immediately after initiation, with profound drops in viremia occurring within the first two weeks of therapy -- perhaps signaling its potency.
Click to enlarge
Reprinted with permission from Hedy Teppler, M.D., et al.
In addition, the drug was well tolerated by most patients. Analysis of the lipid data48 from this trial demonstrate no changes in cholesterol subsets or triglycerides among patients who were assigned MK-0518. In contrast, there were increases seen in total cholesterol and fasting triglycerides among those receiving efavirenz.
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