Top 10 HIV Clinical Developments of 2008 - CD8 T cells - The Body

HIV JournalView A CME/CE Monograph From 

Top 10 

HIV Clinical Developments 

of 2008 

By David Alain Wohl, M.D. 

University of North Carolina 

AIDS Research and Treatment Unit 

Released on Feb. 27, 2009. Jointly sponsored by Postgraduate 

Institute for Medicine and Body Health Resources Corporation. 

Supported by an educational grant from Tibotec Therapeutics. 

Prepared and distributed by The Body PRO. 

The HIV Resource for Health Professionals 

www.thebodypro.com

2 • HIV JournalView—Top 10 HIV Clinical Developments of 2008 

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Table of Contents 

www.thebodypro.com/cme • 3 

Activity Overview, Learning Objectives and Accreditation Information 4 

About the Author 7 

Introduction 8 

Top 10 HIV Clinical Developments of 2008: 

1. The Pendulum Strikes Back—When to (Not) Start HIV Therapy 9 

2. Inflammation = Death 13 

3. Abacavir Redux 17 

4. HIV Cured 21 

5. Coming Soon: New Initial Antiretroviral Choices 23 

6. Why A5164 Is Important 27 

7. Opt-Out Testing at Last? 30 

8. Updated U.S. HIV Incidence 33 

9. Survival in the Time of HAART 36 

10. No Bones About It 39 

The Runners-Up: 

Obama Wins! 43 

Financial Crisis Hurts People Living With HIV 45 

Jesse Helm’s U.S. Travel Ban Lifted 46 

A Diehard AIDS Denialist Dies 47 

Wrap-Up 48 

References 49 

CME/CE Post-Test, Course Evaluation and Credit Application 53


Activity Overview, Learning Objectives and Accreditation Information 

Activity Title 

Top 10 HIV Clinical Developments of 2008 

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This continuing-education activity consists of one article (see Required Materials section below) and a post-test consisting of 7 

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The purpose of this activity is to provide HIV physicians, pharmacists, nurses and other health care professionals with the 

opportunity to supplement their knowledge on issues related to HIV treatment, complications of HIV/HAART, HIV epidemiology and 

HIV prevention. This will be accomplished via a CME/CE summary of significant clinical developments that occurred during the 

2008 calendar year. 

Target Audience 

This activity has been designed to meet the educational needs of physicians, pharmacists, registered nurses and other health care 

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Objectives 

Participants who complete this educational activity should be able to: 

1. Explain the possible clinical ramifications of the most significant HIV-related studies, reports and other clinical developments in 

HIV that took place in 2008. 

2. Recount the latest developments regarding the efficacy and toxicity of HIV antiretroviral agents, HAART regimens and treatment 

strategies, based on vital research published or presented in 2008. 

3. Describe the results of selected research developments in 2008 regarding the transmission or acquisition of HIV. 

4. Cite the findings of key, selected studies published or presented in 2008 regarding morbidities and mortality in HIV-infected persons. 

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2. Read the Required Article. 

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4. Complete the course evaluation survey and credit application, which are included in this booklet.


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Top 10 HIV Clinical Developments of 2008 CME/CE 

TheBodyPRO.com 

250 West 57th Street, Suite 1614 


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About the Author 

David Alain Wohl, M.D. 

Dr. Wohl is an associate professor of medicine at the University of North 

Carolina at Chapel Hill, and co-directs HIV services for the North Carolina 

Department of Corrections. Dr. Wohl is an investigator in the NIAIDsponsored 

AIDS Clinical Trials Group (ACTG) and a member of the ACTG 

Complications of HIV Disease Research Agenda Committee. His research 

focuses on metabolic and infectious complications of HIV and its therapies, 

as well as issues related to medication adherence and access to care— 

particularly among incarcerated inmates with HIV infection. 

After graduating from Boston University in 1986 and receiving an additional 

Bachelor of Science degree from the Touro College of Biomedical Education 

in 1988, Dr. Wohl completed his medical education at Robert Wood Johnson 

Medical School in 1991. He finished residency in internal medicine at Duke 

University in 1994, after which he began a three-year infectious diseases 

fellowship at the University of North Carolina-Chapel Hill. He joined the UNC- 

Chapel Hill faculty shortly thereafter, and hasn’t looked back since. 

Dr. Wohl’s research has appeared in over a half-dozen peer-reviewed journals 

and several clinical texts. He has taken part in several major HIV conferences, 

including the 2001 meeting of the International AIDS Society-USA and the 

International AIDS Conference in Barcelona, where he co-authored a study on 

risk behaviors among HIV-infected former prisoners. 

Dr. Wohl has won three awards in recent years for his HIV-related research, 

including the John Carey Young Investigator Award from the National Institutes 

of Health’s AIDS Clinical Trials Unit. 

Disclosures 

Dr. Wohl has been a consultant for Abbott Laboratories, Tibotec Therapeutics 

and Merck & Co. He has served on speakers bureaus for Abbott, Gilead, 

Roche Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec 

Therapeutics and Merck. In addition, he has received research support from 

Abbott, Roche and Merck. 

www.thebodypro.com/cme • 7


Introduction 

Why recap the top 10 stories in HIV management from 2008? 

Because, in an unprecedented year of anxiety and elation, when we 

embraced change and clung to the right to hope that it would lead us 

to a better place, we are obligated to look at what we have learned 

and linger on the results that show us the remarkable progress we 

made in combating HIV, as well as what more we can and must do. ª

1 

The Pendulum 

Strikes Back— 

When to (Not) 

Start HIV Therapy 

A review of: 

Initiating rather than deferring HAART at a CD4+ 

count between 351-500 cells/mm3 is associated 

with improved survival. M. M. Kitahata, S. J. Gange, 

R. D. Moore, The North American AIDS Cohort 

Collaboration On Research And Design. In: Program 

and abstracts of the 48th Annual ICAAC/IDSA 46th 

Annual Meeting; October 25-28, 2008; Washington, 

D.C. Abstract H-896b. 


I 

t is remarkable that decades into the HIV epidemic we 

still find ourselves swinging back and forth regarding 

some fundamental medical decisions. At the dawn 

of the epidemic, empiricism led us to prescribe 

antiretroviral therapy early after diagnosis. But since 

March of 1987, when the first antiretroviral zidovudine 

(AZT, Retrovir) was approved, the treatment landscape 

has shifted continually—often dramatically—and, 

ironically, as potent and durable antiretrovirals were 

developed, prudence, caution and a bit of data stayed 

our prescribing hand. 

The best data we have had to inform our decisions 

regarding the timing of HIV therapy initiation were 

observational and not considerably long term. Assessing 

the therapeutic benefits of early treatment initiation has 

been challenging when the very drugs being utilized have 

changed so quickly. Clearly, it has been understood for 

some time that to wait until a patient’s CD4+ cell count 

fell to less than 200 cells/mm 3 was to wait too long. But 

there were fewer dots to connect to indicate the optimal 

point at which to attack the virus. 

And our eagerness to pull the antiretroviral trigger has 

been chastened as we witnessed the hollowed cheeks, 

the dyslipidemia, the glucose intolerance and the elevated 

hepatic transaminases of our patients. Like beginners in 

a chess game, we learned to hold back and resist moving 

our powerful queen across the board at the opening. 

Yet, some impressive recent observations have reopened 

the when-to-start discussion and highlighted the benefits 

of initiating HIV treatment in patients at a higher CD4+ cell 

count. 

The Antiretroviral Therapy Cohort Collaboration, which 

contains data from cohort studies in North America and 

Europe, looked at more than 61,000 HIV-infected patients. 

In a study by Margaret May et al that was published in 

the journal AIDS, the investigators found a reduced risk 

of AIDS progression and/or death among patients who 

started HIV treatment at a CD4+ cell count of between 

200 and 350 cells/mm 3 compared to those who initiated 

therapy at a CD4+ cell count of less than 200 cells/mm 3 . 1 

Other studies have showed a progressively diminished 

risk of HIV-related and non-AIDS-associated events

10 • HIV JournalView—Top 10 HIV Clinical Developments of 2008 

when treatment is initiated at CD4+ cell counts 

between 200 and 350 cells/mm 3 . 2-9 Such findings 

have been a part of the motivation for the current 

350 cells/mm 3 line in the sand that both the U.S. 

Department of Health and Human Services (DHHS) 

and the International AIDS Society-USA (IAS-USA) 

endorse. 10,11 

But what about treatment initiation at higher CD4+ 

cell counts? With the simplicity and potency of current 

antiretroviral regimens and our increasing comfort with 

the lower (apparent) risk of the long-term toxicity of 

these drugs, should patients be treated sooner in their 

HIV course? 

Most significantly, the landmark Strategies 

for Management of Antiretroviral Therapy 

(SMART) Study opened up a super-sized can 

of whoop ass on our assumptions regarding 

the toxicity of HIV medications relative to 

the adverse effects of nasty ole HIV itself. 

However, while teaching us that stopping 

HIV therapy at a high CD4+ cell count was a 

bad idea, it also whispered sweet somethings 

in our ear about the well-being of untreated 

patients with similar CD4+ cell counts. 12 

FIGURE 1 

Thus, here we stand, feet rooted in the 

evidence-based and guideline-specified 

while our heads we scratch. That state of 

equipoise could change with a soon-to-be 

published report from the North American 

AIDS Cohort Collaboration on Research and 

Design (NA-ACCORD). 13 The results of this 

observational study—comparing all-cause 

mortality among participants who initiated 

antiretroviral therapy at CD4+ cell counts 

between 351 and 500 cells/mm 3 and those who 

started HAART (highly active antiretroviral therapy) at 

counts at or less than 350 cells/mm 3 —were presented 

by Mari M. Kitahata at ICAAC/IDSA 2008 in October 

(the 48th Annual ICAAC/IDSA 46th Annual Meeting) 

and stole that show. 

Over 8,300 HIV-infected patients in the United States 

and Canada with CD4+ cell counts between 351 to 

500 cells/mm 3 while in active follow-up between 1996 

and 2006 were included in the analysis. 

A feature of the NA-ACCORD investigation was the 

attempt to minimize lead-time bias—i.e., the bias that 

exists when events that occurred prior to study entry 

(such as death) are missed. To reduce such bias, the 

analysis included patients who had CD4+ cell counts 

greater than 350 cells/mm 3 —whether they initiated HIV 

therapy (within 18 months of their first CD4+ cell count 

in that range) or deferred starting HIV therapy in the same 

time frame. The latter includes patients who started HIV 

therapy when their CD4+ cell counts dropped to less than 

350 cells/mm 3 , as well as patients who delayed initiating 

treatment for several years after reaching this target CD4+ 

cell count, never initiated HIV treatment, or died. 

Most patients included in the analysis were male and about 

60% were non-white. Overall, there were almost 25,000 

person-years of follow-up. Among patients who started HIV 

therapy, most initiated therapy with an unboosted protease 

inhibitor (PI) or a non-nucleoside reverse transcriptase 

inhibitor (NNRTI)-based regimen. 

In their analysis, the NA-ACCORD team discovered 

that starting HIV therapy at a CD4+ cell count 

greater than 350 cells/mm 3 was associated with 

a 70% improvement in survival (relative hazard 

[RH]: 1.7; 95% confidence interval [CI], 1.4-2.1; P < 

.001)—an effect that persisted even after adjusting 

for factors associated with impaired survival 

(e.g., injection drug use, hepatitis C virus [HCV] 

coinfection). Older age, a history of injection drug use and 

HCV infection were associated with mortality. In patients 

who received HIV therapy (immediate or deferred), HIV 

RNA levels were similar, suggesting differential adherence 

to treatment is not likely to be playing a role. 

The Bottom Line 

These are incredibly important results with wide-ranging

implications. The study indicates that a starting threshold 

for HIV therapy of 350 cells/mm 3 is too low and, more 

importantly, that deaths can be prevented with earlier 

initiation of HIV therapy. 

There are several reasons to believe these results. 

Foremost, is the carefully considered study design to 

reduce bias and the sophisticated analytical techniques 

that were employed. Furthermore, the number of patients 

studied was large and included a substantial number of 

untreated patients. 

Yet, there are those who point out that this was an 

observational, and not a randomized, trial. Medicine has 

been led astray before when placing too much faith on 

cohort data (witness the use of hormone replacement 

therapy in post-menopausal women to prevent 

cardiovascular disease 14 ). Covert biases and imbalances 

can be present in such studies and remain unaccounted 

for. 

For example, could it be that the patients in the NA-ACCORD 

who defer HIV therapy are different from the patients who are 

more eager to be treated in ways that we cannot measure? 

It appears that the patients who deferred therapy and 

maintained a CD4+ cell count greater than 350 cells/mm 3 

had the greatest risk of death—more so than patients whose 

CD4+ cell counts fell below this level. 

That the risk of death was strong (if not, strongest) among 

patients who were not receiving therapy, but who had 

FIGURE 2 


high CD4+ cell counts, is one of the mysterious, if not 

scariest, aspects of this study. One wonders whether 

people who deferred treatment had other unobserved 

life-threatening lifestyle traits or characteristics (call it the 

“hard-luck” factor). Unfortunately, the causes of death 

were not presented at ICAAC/IDSA 2008 and, as of this 

writing, remain unpublished. More information regarding 

these and other patient deaths will be of interest. 

The cynic will point out that the median CD4+ cell count 

at presentation in the United States is a pitiful 200 to 276 

cells/mm 3 and thus, arguments about when to start HIV 

therapy are irrelevant, if not moot. 15 True, opportunities 

to detect HIV infection are all too often missed, but a 

significant number of individuals are discovered to be HIV 

infected at much higher CD4+ cell counts, such as when 

they are incarcerated, apply for life insurance or (one 

hopes) present to a sexually transmitted disease clinic. 

(See top story number seven.) 

Indeed, the 2006 U.S. Centers for Disease Control and 

Prevention (CDC) recommendations for increased HIV 

screening in medical settings state as their goal the 

diagnosis of HIV earlier in its course. 16 

These data may be strengthened when the NA-ACCORD 

researchers present their latest data at the Conference 

on Retroviruses and Opportunistic Infections (CROI) in 

February 2009. Their expected presentation will examine 

the effect of starting patients on antiretrovirals at a CD4+ 

cell count greater than 500 cells/mm 3 . Similarly, if other 

cohort studies present analyses 

supporting these results, NA- 

ACCORD will be impossible to 

discount. 

Another trial that has long been 

anticipated is known as the 

START (Strategic Timing of 

AntiRetroviral Treatment) Trial. 

This trial hopes to answer the 

question regarding when is the 

ideal time to initiate therapy. The 

study, which is a randomized 

study of early versus delayed 

initiation of HIV therapy, will 

be one of the most watched 

(and possibly dramatic) stories 

of 2009. What it will mean to 

clinicians depends on their own 

faith in the data once published, 

examined and explained. 

For this physician—generally


inclined to fall on the more aggressive side in offering HIV 

treatment to willing patients with CD4+ cell counts in the 

netherworld of 350 to 500 cells/mm 3 —the NA-ACCORD 

findings are validating and in time may inspire treatment 

at even higher CD4+ cell counts, especially given recent 

concerns regarding the relationship between HIV viremia 

and inflammation, which brings us to the second top story 

of 2008. ª 

Study Snapshot: When to Start HIV Therapy (NA-ACCORD Study) 

Design: Observational cohort study of HIV-infected patients in Canada and the United States. 

Population: Over 8,300 HIV-infected patients with CD4+ cell counts between 351 to 500 cells/mm 3 . 

Main Results: Starting HIV therapy at a CD4+ cell count greater than 350 cells/mm 3 was associated with a 70% 

improvement in survival (RH: 1.7; 95% CI, 1.4-2.1; P < .001)—an effect that persisted even after adjusting for factors 

associated with impaired survival (e.g., injection drug use, HCV coinfection). 

Significance: Indicates that a starting threshold for HIV therapy of 350 cells/mm 3 is too low and, more importantly, that 

deaths can be prevented with earlier initiation of HIV therapy.

Inflflflflflflflflfl 

2 

flffllammation = Death 


Inflammatory and coagulation biomarkers and 

mortality in patients with HIV infection. Lewis H. 

Kuller, Russell Tracy, Waldo Belloso, Stephane 

De Wit, Fraser Drummond, H. Clifford Lane, 

Bruno Ledergerber, 

FIGURE 3 

Jens Lundgren, 

Jacqueline 

Neuhaus, Daniel 

Nixon, Nicholas I. 

Paton, James D. 

Neaton, for the 

INSIGHT SMART 

Study Group. 

PLoS Medicine. 

October 21, 2008; 

5(10):e203. 


If gray was the new black, and now brown is the new 

gray, and plaid is what people who supported Dennis 

Kucinich wear, then HIV-associated inflammation is 

the new metabolic complications. Tellingly, evaluations 

using markers of inflammation are becoming standard 

issue in HIV clinical trials and researchers neglecting to 

include such assays will be regarded with pity. 

That HIV infection may lead to the proliferation of 

pro-inflammatory humors within the body is not a new 

idea. But the relationship between certain cytokine levels, 

as well as markers of coagulation, and cardiovascular 

disease (CVD) and mortality in the SMART study of 

treatment interruption, is having a profound influence on 

the management of HIV disease. 12 

Most significantly, the SMART study demonstrated the 

hazards of treatment interruption, even at decent CD4+ cell 

counts, and made plain the pernicious effects of the virus.


The surprising finding that patients who were not receiving 

HIV therapy suffered a greater risk of non-AIDS-related 

adverse events and death than those who maintained 

antiretroviral treatment, however, was never understood. 

Exactly what was the mechanism behind this increased 

risk of bad things happening? 

In their anticipated follow-up investigations, the SMART 

study team provides a very plausible explanation by 

looking at the state of inflammation and coagulation in 

the study arms. 17 In a clever, but complicated, pair of 

investigations, the levels of several validated and reliable 

markers of inflammation and coagulation, previously 

linked to CVD in the general population, were examined. 

These markers include interleukin-6 (IL-6), high sensitivity 

C-reactive protein (hs-CRP), amyloid A, amyloid P, 

D-dimer and prothrombin fragment 1 and 2. 

One study was a nested case control study, in which marker 

level data that had been collected from 85 participants who 

died (55 were in the discontinuation of HIV therapy arm, the 

remainder in the continuation arm) were compared to two 

controls who did not die per each case matched by age, 

gender, geographic location and date randomized on study. 

The other study was a comparison of the changes in 

these markers between each of the two study arms using 

a sample of about 250 participants without known prior 

CVD. 

FIGURE 4 

In the nested case control study, levels of each marker 

were examined at baseline in both cases and control 

study participants. Among the cases, 74 had specimens 

available from their study visit before their death. These 

were compared to specimens collected from the controls 

at the same follow-up visit. At baseline, the levels of 

almost all markers were higher in patients who 

died (cases) than in the controls. IL-6 and D-dimer 

stood out as most significantly different between 

patients who died and those who did not. 

Unadjusted odds ratios (highest versus lowest quartile) for 

hs-CRP, IL-6 and D-dimer were 2.0 (95% CI, 1.0-4.1; P 

= .05), 8.3 (95% CI, 3.3-20.8; P < .0001) and 12.4 (95% 

CI, 4.2-37.0; P < .0001), respectively. The association 

between baseline levels of these markers and mortality was 

evident even when looking at the study arms separately. 

When focusing on biomarker levels at the study visit 

before death in the cases and at the corresponding 

visit for the control study participants, the story 

was the same: Those who died did so with higher 

levels of most of these markers. For both the baseline 

and final analyses of the biomarker levels and mortality, 

multivariable analysis accounting for covariates such as 

demographic characteristics, HIV RNA levels, CD4+ 

cell counts, CVD risk factors and coinfection with viral 

hepatitis did not appreciably alter the associations between 

biomarkers and risk of death. 

While the nested study confirms 

that markers of inflammation and 

coagulation are likely to be found 

in patients with worse fates, 

the comparison of the changes 

in these markers during the 

study found that both IL-6 and 

D-dimer levels increased by 

30% and 16%, respectively, 

at the one-month mark 

in the discontinuation of 

antiretroviral therapy arm 

compared to no change in 

IL-6 and only a 5% increase 

in D-dimer among trial 

participants who were 

maintaining their HIV therapy 

(P < .0001 for both markers). 

Changes in patients’ biomarkers 

in the treatment interruption arm 

were strongly correlated with 

changes in HIV viremia. Patients 

who started the trial with low viral

loads and discontinued treatment saw the greatest rise in 

their biomarker levels. Based on models of mortality 

risk generated from the baseline biomarker data, the 

differences in the change in levels in the study arms 

are predicted to lead to a 16% to 24% increased risk 

of death for those stopping antiretroviral therapy. 


While it may be no great surprise that HIV-infected 

people with unchecked HIV viremia—and attendant 

immune activation—would have higher levels of circulating 

markers of inflammation, these data pin an attractively 

reasonable causative mechanism to the potentially 

catastrophic effects of treatment cessation. 

It is notable that the baseline CD4+ cell counts of the cases 

(i.e., patients who died during the study) were close to 600 

cells/mm 3 and that most died of non-AIDS-related events. 

The cause of these fatal outcomes demands an explanation 

and this analysis points to a new way to view the threats 

to the well-being of patients who, despite robust immune 

function, have suboptimally controlled HIV infection. 

Furthermore, the result has irrevocably established 

endothelial dysfunction as a dimension of the 

management of HIV disease. Specifically, the effects 

of the virus and, more acutely, the relative abilities of 

antiretroviral FIGURE 5 

agents to 

moderate (or 

even contribute 

to) inflammation 

have fueled, and 

will continue to 

fuel, much of 

the discussion 

regarding the 

optimal timing and 

composition of 

HIV therapy. (See 

top story number 

three.) 

Studies 

conducted 

among the 

HIV-uninfected 

have taught us 

that persistent 

pro-inflammatory 

states are 

associated with 

life-threatening 

illnesses, 


including CVD, peripheral vascular disease and diabetes. 

As mentioned above, the finding of a spike in inflammatory/ 

coagulation biomarkers with treatment cessation, above 

and beyond that seen with ongoing viral replication and 

its strong association with death, has implications for the 

ongoing debate regarding when to start HIV therapy. 

Already, the findings from the SMART study have all but 

driven a wooden stake through the heart of prescribed 

treatment holidays, while simultaneously provoking anxiety 

in clinicians whose patients self-discontinue their HIV 

therapy due to tolerability issues, a chaotic life or financial 

reasons. (See runners-up section.) 

Some investigators are looking at the use of anti-inflammatory 

agents during these treatment discontinuations to counter 

inflammation. This may lead to helpful interventions to bridge 

periods when antiretroviral therapy is not possible. 

Clearly, there is more to be done and, as was the case 

with mitochondrial dysfunction, the study of endothelial 

dysfunction will bring new researchers from other fields 

into the HIV tent and provide a fresh appreciation for the 

need to reduce inflammation, be it fanned by the virus, 

horrid dentition, genes or a certain nucleoside reverse 

transcriptase inhibitor (NRTI)—or not, read on. ª


Study Snapshot: Inflammatory and Coagulation Biomarkers and Mortality in 

INSIGHT SMART Study Groups 

Design: A pair of investigations were conducted: (1) a nested case-control study of HIV-infected INSIGHT SMART participants 

for studying biomarker associations with mortality, and (2) a study to compare drug conservation versus viral suppression 

participants for biomarker changes. 

Population: (1) 85 participants who died (55 were in the discontinuation of HIV therapy arm, the remainder in the continuation 

arm) compared to two controls who did not die per each case. (2) About 250 participants without known prior CVD. 

Main Results: The combined results show that, at baseline, the levels of almost all markers were higher in patients who died 

(cases) than in the controls. IL-6 and D-dimer stood out as most significantly different between patients who died and those 

who did not. Based on models of mortality risk generated from the baseline biomarker data, the differences in the change in 

levels in the study arms are predicted to lead to a 16% to 24% increased risk of death for those stopping antiretroviral therapy. 

Significance: Both investigations pin an attractively reasonable causative mechanism to the potentially catastrophic effects of 

treatment cessation. Point to a new way to view the threats to the well-being of patients who, despite robust immune function, 

have suboptimally controlled HIV infection. Irrevocably establish endothelial dysfunction as a dimension of the management of 

HIV disease.

Abacavir Redux3 


Use of nucleoside reverse transcriptase inhibitors and risk 

of myocardial infarction in HIV-infected patients enrolled in 

the D:A:D study: a multi-cohort collaboration. D:A:D Study 

Group. The Lancet. April 26, 2008;371(9622):1417-1426. 

ACTG 5202: shorter time to virologic failure (VF) with abacavir/ 

lamivudine (ABC/3TC) than tenofovir/emtricitabine (TDF/FTC) 

as part of combination therapy in treatment-naive subjects with 

screening HIV RNA ≥ 100,000 c/mL. P. Sax, C. Tierney, A. 

Collier, M. Fischl, C. Godfrey, N. Jahed, K. Droll, L. Peeples, L. 

Myers, G. Thal, J. Rooney, B. Ha, W. Woodward, E. Daar. In: 

Program and abstracts of the XVII International AIDS Conference; 

August 3-8, 2008; Mexico City, Mexico. Abstract THAB0303. 

Efficacy and safety of abacavir/lamivudine compared to tenofovir/ 

emtricitabine in combination with once-daily lopinavir/ritonavir 

through 48 weeks in the HEAT study. Kimberly Smith, D. Fine, 

P. Patel, N. Bellos, L. Sloan, P. Lackey, D. Sutherland-Phillips, 

C. Vavro, Q. Liao, M. Shaefer. In: Program and abstracts of the 

15th Conference on Retroviruses and Opportunistic Infections; 

February 3-6, 2008; Boston, Mass. Abstract 774. 

Use of nucleoside reverse transcriptase inhibitors and 

risk of myocardial infarction in HIV-infected patients. The 

SMART/INSIGHT and the D:A:D Study Groups. AIDS. 

September 12, 2008;22(14):F17-F24. 

Is abacavir (ABC)-containing combination antiretroviral therapy 

(CART) associated with myocardial infarction (MI)? No association 

identified in pooled summary of 54 clinical trials. A. Cutrell, J. 

Hernandez, J. Yeo, C. Brothers, W. Burkle, W. Spreen. In: Program 

and abstracts of the XVII International AIDS Conference; August 

3-8, 2008; Mexico City, Mexico. Abstract WEAB0106. 

Abacavir/lamivudine (ABC/3TC) shows robust virologic responses 

in ART-naive patients for baseline (BL) viral loads (VL) of ≥ 100,000 

c/mL and < 100,000 c/mL by endpoint used in ACTG5202. K. 

Pappa, J. Hernandez, B. Ha, M. Shaefer, C. Brothers, Q. Liao. In: 

Program and abstracts of the XVII International AIDS Conference; 

August 3-8, 2008; Mexico City, Mexico. Abstract THAB0304. 


This will be mercifully short. Too much has already 

been written about the dimming of abacavir 

(ABC, Ziagen)’s star this year. However, this is 

a big story of 2008 that has spun the heads of 

clinicians, elicited fierce commentary, sparked spirited 

letter writing and left patients who are tuned into the 

drama eyeing their meds suspiciously. 

The facts are well known: 

At the February 2008 CROI in Boston, the D:A:D (The 

Data Collection on Adverse Events of Anti-HIV Drugs) 

study group presented an analysis of associations 

between nucleoside analog exposure and the risk of 

myocardial infarction (MI). They found that rates of MI 

were 90% and 49% greater among patients who had 

recent exposure to abacavir or didanosine (ddI, Videx), 

respectively, relative to those without recent use of these 

agents—data that were later published in The Lancet. 18 

By the end of February, abacavir’s troubles were 

compounded by an announcement from the AIDS 

Clinical Trials Group (ACTG) study A5202. A5202 

is a randomized, placebo-controlled trial of abacavir/ 

lamivudine (ABC/3TC, Epzicom, Kivexa) versus tenofovir/ 

emtricitabine (TDF/FTC, Truvada) co-administered with 

either ritonavir (RTV, Norvir)-boosted atazanavir (ATV, 

Reyataz) or efavirenz (EFV, Sustiva, Stocrin). A decision 

was made to unblind participants who had HIV RNA 

levels more than 100,000 copies/mL following the 

recommendation of a data and safety monitoring board. 

The board had discovered excessive rates of virologic 

failure among patients in the 100,000 copies/mL stratum 

who had been randomized to abacavir/lamivudine. 

These data were presented in detail at the International 

AIDS Conference (IAC) in August and included an 

analysis based on the time to virologic failure in the high 

viral load patients (N = 797) that found that those who 

had been assigned to abacavir/lamivudine had a greater 

risk of failure (HR = 2.33; 95% CI, 1.46-3.72; P < .01) 

compared to those who had been assigned to tenofovir/ 

emtricitabine. 19 

However, in contrast to A5202, another trial known as the 

HEAT Trial, which looked at abacavir/lamivudine versus


FIGURE 6 

tenofovir/emtricitabine in combination with 

lopinavir/ritonavir (LPV/r, Kaletra), found no 

significant difference in virologic efficacy between 

the two study arms (total N = 688, with 393 

having a viral load of 100,000 copies/mL or more 

at study entry). 20 Levels of hs-CRP and IL-6 fall 

in a similar manner in both study arms during the 

course of the trial. 

Yet another study examining abacavir was also 

presented at IAC. The study, by the D:A:D 

study group in collaboration with SMART 

study researchers, examined more than 2,700 

participants in the continuous drug therapy 

arm of the SMART trial to determine whether 

either abacavir or didanosine was associated 

with MI or other CVD events. 21 

FIGURE 7 

In this study, abacavir—but not didanosine— 

was associated with various definitions of 

CVD. As in the D:A:D study, the deleterious 

impact of abacavir was greatest in patients 

who had greater CVD risk. These results were later 

published in the journal AIDS and include a controversial 

sub-study of hs-CRP and IL-6, which suggested higher 

baseline levels of these markers, at least in some of those 

who were receiving abacavir. 

Also at IAC, the maker of abacavir/lamivudine presented 

two retrospective studies in response to the D:A:D 

and A5202 results. The first study culled data from 54 

industry-sponsored trials and found no link between 

abacavir and MI or CVD. 22 

The second study examined virologic outcomes 

using the A5202 definitions of virologic failure 

across six clinical trials of abacavir/lamivudine 

and found high rates of efficacy of the drug and 

minimal difference in treatment response by 

baseline viral load. 23 


Clearly, 2008 was a tough year for conservative 

Republicans, anyone with a 401K and abacavir. 

The conflicting data regarding the safety and 

efficacy of abacavir have led to confusion 

among patients and their clinicians. The data 

are complicated and, understandably, few 

health care providers are blessed with a deep 

understanding of the analytical approaches used 

in each study—leading to a default reliance on 

a gut instinct. This faith-based approach has 

many eschewing abacavir, never a very popular 

nucleoside, given the clouds hanging over it. 

Others, however, lament the de facto monopoly of tenofovir 

(TDF, Viread) as a preferred nucleoside if abacavir is avoided 

and justifiably raise concerns about the ambiguously 

described overlap between the SMART and D:A:D data 

sets, the inclusion of “probable” CVD events in the D:A:D 

study and the risk of uncontrolled channeling bias. 

The debate has become heated. Criticism leveled at 

the data has, at times, crossed over to criticism of the 

investigators. The D:A:D study team, in particular, has left 

itself vulnerable to distracting accusations of being less 

than forthcoming and defensive.

In such times, we look to the experts and the major U.S. 

HIV treatment guideline panels. Both DHHS and IAS-USA 

continue to list abacavir as a nucleoside for use as 

initial HIV therapy. 10,11 In the DHHS guideline, abacavir/ 

lamivudine is considered an alternative to tenofovir/ 

emtricitabine—a position that it can be argued reflects 

the current clinical practice of generally using abacavir 

in patients for whom tenofovir is less desirable. In their 

guideline, the IAS-USA continues to consider abacavir/ 

lamivudine as a recommended agent along with tenofovir/ 

emtricitabine, but they have added caveats regarding 

patients who have higher viral loads and are at risk for CVD. 

With the mixed results of the various studies conducted 

to date, it is difficult to imagine that more data will provide 

a tiebreaker that will reconcile the abacavir debate. 

However, focused and rigorous studies of pathogenesis— 

including additional investigations of the relative effects 

of abacavir and tenofovir on a host of inflammatory/ 

coagulation markers and endothelial function—could 

very well tip the balance either way depending on what 

is discovered. Similarly, there are other large cohorts 

of treated HIV-infected patients and, in the light of the 

Study Snapshot: A5202 


current data gaps and study design concerns, these 

studies could prove informative. 

Meanwhile, in the clinic, I have become increasingly 

cautious about discontinuing abacavir. The aphorism “the 

plural of anecdote is not data” aside, I have regretted 

recent misadventures in messing with the abacavir of 

stable patients—even those with significant CVD risk 

factors. In one case, a long-suppressed patient who 

had been on an initial regimen of zidovudine/lamivudine/ 

abacavir (AZT/3TC/ABC, Trizivir) plus efavirenz, 

experienced a rebound in HIV viremia when his regimen 

was switched to zidovudine/lamivudine (AZT/3TC, 

Combivir) plus efavirenz. In another case, when a patient 

who had been on abacavir/lamivudine and efavirenz was 

changed to a new regimen that included the integrase 

inhibitor raltegravir (MK-0518, Isentress), his pharmacy, 

confused by a similarity in names, mistakenly gave him 

zidovudine instead of the integrase inhibitor. 

Caught in the headlights of opposing data, I, like many, remain 

frozen. However, as opposed to the witless deer, it may be a 

safer thing for a clinician to do, at least regarding abacavir. ª 

Study Snapshot: NRTIs and Myocardial Infarctions in D:A:D Study 

Design: International, prospective, observational cohort study assessing the risk of MI among patients exposed to NRTIs. 

Population: 33,347 HIV-infected patients from 188 clinics in 21 countries in Europe, the United States and Australia. 

Main Results: Over 157,912 person-years. 517 patients had a MI. Rates of MI were 90% and 49% greater among patients who 

had recent exposure to abacavir or didanosine, respectively, relative to those without recent use of these agents. 

Significance: Results showed abacavir and didanosine increase MI risk. Excess risk did not seem to be explained by underlying 

established cardiovascular risk factors and was not present beyond six months after drug cessation. 

Design: Randomized, placebo-controlled trial of abacavir/lamivudine vs. tenofovir/emtricitabine co-administered with either 

ritonavir-boosted atazanavir or efavirenz. 

Population: 1,858 HIV-infected patients; 797 had screening HIV-RNA ≥ 100,000 copies/mL. 

Main Results: Those who had been assigned to abacavir/lamivudine had a greater risk of failure (HR = 2.33; 95% CI, 1.46-3.72; 

P < .01) compared to those who had been assigned to tenofovir/emtricitabine. 

Significance: Results showed a significantly shorter time to virologic failure and grade 3/4 adverse events in patients randomized to abacavir/ 

lamivudine. Comparisons of blinded NRTIs in the lower HIV-RNA stratum and each regimen’s third drug in both strata are ongoing.


Study Snapshot: HEAT 

Design: Randomized, double-blind, placebo-matched, multi-center, 96-week, non-inferiority study. Patients received either 

blinded abacavir/lamivudine or tenofovir/emtricitabine with open-label lopinavir/ritonavir soft gel capsule once daily. 

Population: 688 HIV-1-infected, antiretroviral-naive patients had a plasma HIV-1 RNA ≥ 1,000 copies/mL, (stratified < or ≥ 

100,000 copies/mL), and any CD4+ count. Mean age was 38 years; 18% were female. 

Main Results: No significant difference in virologic efficacy between the two study arms. Levels of hs-CRP and IL-6 fall in a 

similar manner in both study arms during the course of the trial. 

Significance: Contradicts A5202 findings that showed a significantly shorter time to virologic failure and grade 3/4 adverse 

events in patients randomized to abacavir/lamivudine. 

Study Snapshot: NRTIs and Risk of Myocardial Infarction in INSIGHT SMART 

and D:A:D Study Groups 

Design: Exploratory study of biomarkers, ischemic changes on the electrocardiogram and rates of various predefined types of 

CVD events according to NRTIs used in SMART study. Patients receiving abacavir and not didanosine were compared with 

those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine. 

Population: 2,752 participants in the continuous drug therapy arm of the SMART trial. 

Main Results: Abacavir—but not didanosine—was associated with various definitions of CVD. As in the D:A:D study, the 

deleterious impact of abacavir was greatest in patients who had greater CVD risk. 

Significance: Showed abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which 

may precipitate a CVD event. 

Study Snapshot: Review of 54 Industry-Sponsored Trials 

Design: Pooled summary of 54 industry-sponsored trials with ≥ 24 weeks of combination antiretroviral therapy (CART) with and 

without abacavir. 

Population: 14,683 HIV-infected patients who received abacavir-containing CART (N = 9,639; 7,845 person-years) or 

non-abacavir-containing CART (N = 5,044; 4,653 person-years). 

Main Results: No higher risk of myocardial infarction associated with abacavir-containing CART was identified in this review. 

Significance: Contradicts D:A:D and A5202 study results. 

Study Snapshot: Review of Six Clinical Trials 

Design: Pooled summary of 48-week efficacy data from six clinical trials of abacavir/lamivudine using the A5202 definitions of 

virologic failure. 

Population: 2,940 antiretroviral-naive patients. 

Main Results: High rates of efficacy with abacavir/lamivudine and minimal difference in treatment response by baseline viral load. 

Significance: Contradicts D:A:D and A5202 study results.

HIV Cured 

4 


Treatment of HIV-1 infection by allogeneic 

CCR5-D32/D32 stem cell transplantation: a 

promising approach. Gero Hutter, D. Nowak, M. 

Mossner, S. Ganepola, K. Allers, T. Schneider, J. 

Hofmann, I. Blau, W. K. Hofmann, E. Thiel. In: Program 

and abstracts of the 15th Conference on Retroviruses 

and Opportunistic Infections; February 3-6, 2008; 

Boston, Mass. Abstract 719. 


It is tempting to be somewhat dismissive of yet 

another claim of a man in Europe being cured of his 

HIV infection, but the report—which passed under 

the radar at CROI 2008 24 and months later was 

described in The Wall Street Journal—of an HIV-infected 

American with leukemia and persistently unrecoverable 

HIV following a stem cell transplant, is a big deal—if not 

to you, then to your patients. 

The specifics are beautiful in their simplicity. The 

patient, a 40-year-old HIV-infected man working in 

Germany, was diagnosed with acute myeloid leukemia 

(AML) in 2006. He had been infected with HIV since 

at least 1995. After a relapse following conventional 

chemotherapy, the patient was prepared for bone 

marrow transplantation. 

Cleverly, the patient’s hematologist suggested that a 

donor homozygous for the CCR5-delta 32 mutation— 

linked to an absence of CCR5 co-receptors on the 

lymphocyte surface—be sought since the patient’s 

virus was CCR5 tropic. The homozygous CCR5-delta 

32 mutation is rare, occurring in about 1% of Central 

Europeans, but a match with the co-receptor deletion 

was eventually found. 

Following standard chemotherapy and radiation, 

the transplant was performed and HIV therapy was 

discontinued to avoid marrow toxicity. Plans were 

made to resume antiretrovirals once viral rebound was 

detected. However, to everyone’s surprise, viral rebound 

was never detected. 

More than 600 days later, the patient has undetectable 

levels of HIV in his peripheral blood, bone marrow and 

rectal mucosa. The patient’s CD4+ cells continue to 

be absent CCR5 receptors. Specimens of the patient’s 

fluids and tissue have been sent across the globe to 

those best able to pick HIV from its pockets to determine 

if there is any evidence of remaining virus. So far, no HIV 

has been found. 


The eradication of HIV, which this case may well 

represent, is the holy grail of the HIV cure industry. As 

the virus establishes latency in slow to replicate cells


FIGURE 8 

early in the course of HIV infection, those attempting to 

rid the body of the virus have tried to either cajole the 

virus from its sanctuaries or kill it along with the cells in 

which it hides. Some will recall the 1980s-era reports of 

bone marrow transplantation and the eradication of HIV; 

however, techniques for the detection of the virus were 

less sophisticated then and the death of patients soon after 

the bone marrow transplant denied opportunities for 

long-term follow-up. 25,26 The interesting combination of 

Study Snapshot: HIV Treatment by Stem Cell Transplant 

Design: Case study. 

cytotoxic therapy and the replacement of bone 

marrow stem cells with CCR5-deficient mutants, 

in this case, is what is novel and most tantalizing. 

Clearly, given the cost and the high risk of 

life-threatening complications, stem cell 

transplantation is not the HIV cure we need, 

or want. For one thing, one third of patients 

undergoing the procedure die. However, the 

results suggest that less dramatic and risky 

interventions are well worth exploring; these 

include such things as gene therapy to alter 

lymphocyte co-receptor expression. 

In addition to the excitement that this case has 

generated among patients and their advocates, 

this report also is noteworthy for the innovative 

and creative thinking of the physicians involved. 

It was a masterstroke of an idea to search for 

a CCR5-delta 32 marrow donor. I would like 

to think that I too would have thought of this in the same 

situation. But, I also like to think I have a full head of hair 

(I don’t), am good with money (I’m not) and have kept 

my youthful attractiveness (you be the judge). These 

clinicians and their patient deserve admiration for a wellconsidered, 

inspired and courageous choice that just 

might provide the keyhole through which an accessible 

cure for HIV can be glimpsed. ª 

Population: 40-year-old man in Germany with HIV-1 infection since 1995 having a relapse of acute myeloid leukemia, first 

diagnosed in 2006. 

Main Results: More than 600 days post-transplant, the patient has undetectable levels of HIV in his peripheral blood, bone 

marrow and rectal mucosa. The patient’s CD4+ cells continue to be absent CCR5 receptors. 

Significance: Given the cost and the high risk of life-threatening complications, stem cell transplantation is not the HIV cure we 

need, or want. However, results suggest that less dramatic and risky interventions are well worth exploring; these include such 

things as gene therapy to alter lymphocyte co-receptor expression.

5 

Coming Soon: New 

Initial Antiretroviral 

Choices 


STARTMRK, a phase III study of the safety & 

efficacy of raltegravir (RAL)-based vs efavirenz 

(EFV)-based combination therapy in treatmentnaive 

HIV-infected patients. J. Lennox, E. DeJesus, 

A. Lazzarin, R. Pollard, J. Madruga, J. Zhao, X. 

Xu, A. Williams-Diaz, A. Rodgers, M. Dinubile, 

B. Nguyen, R. Leavitt, P. Sklar. In: Program and 

abstracts of the 48th Annual ICAAC/IDSA 

46th Annual Meeting; October 25-28, 2008; 

Washington, D.C. Abstract H-896a. 

Reanalysis of the MERIT study with the 

enhanced Trofile assay. M. Saag, J. Heera, J. 

Goodrich, E. DeJesus, N. Clumeck, D. Cooper, 

S. Walmsley, N. Ting, E. Coakley, J. Reeves, M. 

Westby, E. van der Ryst, H. Mayer. In: Program 

and abstracts of the 48th Annual ICAAC/IDSA 

46th Annual Meeting; October 25-28, 2008; 

Washington, D.C. Abstract H-1232a. 

FIGURE 9 


T 

he menu of agents for the initial treatment of HIV 

infection has gone from bare bones to bountiful 

as more and more antiretrovirals ascend from 

the depths of salvage therapy to enter first-line 

paradise. In fact, the number of recommended agents in 

the DHHS guideline has grown to such an extent that 

a list of what not to start would be shorter. In 2008, 

research regarding two potential additions to the initial 

therapy club, raltegravir and maraviroc (MVC, Selzentry, 

Celsentri), were presented. 

Raltegravir 

This integrase inhibitor has always been an initial 

antiretroviral hiding in salvage antiretroviral’s clothing. 

The drug has a low pill burden, few adverse effects and 

relatively scant drug interactions. Transmitted resistance to 

raltegravir is, for now, unknown. A small dose-ranging study 

showcased the ability of raltegravir to hold its own against 

efavirenz in the treatment naive and increasing experience 

with the drug as a centerpiece of salvage regimens has led 

to clinician comfort with this first agent in a wholly novel 

drug class. 

What was missing was the capstone large randomized 

clinical trial. At ICAAC/IDSA 2008, data from the


FIGURE 10 

STARTMRK trial of raltegravir versus efavirenz, when 

taken with tenofovir/emtricitabine, was presented. 27 The 

double-blind study was conducted among treatment-naive 

patients. 

Like most of these kinds of trials, this was a non-inferiority 

study and the outer bounds of the confidence interval 

for the non-inferiority condition to be met was 12%. The 

primary endpoint was a viral load of less than 50 copies/ 

mL at week 48, with non-completer equal to failure. There 

were 563 people in the trial, randomized 1:1 to each 

treatment arm. Trial participants were mostly male and 

non-white. 

At week 48, 86% of patients who had been 

randomized to raltegravir compared to 82% who 

had been assigned to efavirenz achieved a viral 

load of less than 50 copies/mL—a 4% difference 

meeting the condition for non-inferiority. CD4+ 

cell count gains were seen in both arms with a 

statistically significantly greater increase seen 

with raltegravir than efavirenz (189 cells/mm 3 

versus 163 cells/mm 3 , respectively). 

Overall, there were 39 pure virologic failures with 

efavirenz and 27 with raltegravir. Only a fraction of the 

patients had sufficient virus for resistance testing, which 

showed a smattering of mutations associated with 

integrase inhibitors and NNRTIs. 

There were more drug-related adverse events with efavirenz 

compared to raltegravir, with central nervous system toxicity, 

assessed for specifically at study visits, being almost twice 

as common with efavirenz. Raltegravir was more lipid 

friendly compared to efavirenz, except in 

terms of HDL (high-density lipoprotein) for 

which an increase was seen with efavirenz. 

Maraviroc 

Down on its luck, lost amid the cacophonous 

buzz regarding raltegravir and tragically 

attached at the hip to an exorbitantly priced 

laboratory test to determine its utility, maraviroc 

needed to score a home run in its own large 

treatment-naive trial debut. Instead it got a 

base hit and then fouled out. Despite that 

inauspicious start, this may turn out to be the 

little CCR5 inhibitor that (eventually) could. 

The MERIT (Maraviroc versus Efavirenz Regimens 

as Initial Therapy) study compared maraviroc 

with the giant-slayer efavirenz in 740 people who 

were naive to HIV therapy and harboring R5-only 

virus at screening. 28 At 48 weeks, 65.3% of 

the patients who were taking maraviroc had a viral 

load of less than 50 copies/mL versus 69.3% of 

those who were treated with efavirenz (everyone got 

zidovudine/lamivudine). The difference was 4.2%, 

with a lower limit bounds of the 97.5% confidence 

interval that just exceeded the outer bounds for 

non-inferiority of 10%. This means, statistically, there was 

enough of a chance that maraviroc was not non-inferior to 

efavirenz that non-inferiority could not be claimed. 

Subsequently, the investigators have tried to explain these 

results by examining mitigating factors (their version of 

hanging chads). Primarily they have been looking to see if 

there were trial participants who may not have been only 

R5 tropic at baseline (and, therefore, not candidates for 

this agent) and if so, how removing them from the analysis 

would change the results. 29 

From the time of the screening visit to the study entry 

visit, 25 (3.5%) of the cohort had a tropism assay 

result change from R5 to dual/mixed (11 of these were 

in the maraviroc arm). As expected, if patients with 

dual/mixed virus detected during the study are 

excluded, the difference in the proportion with 

a viral load of less than 50 copies/mL narrows 

between the arms. However, this fails to explain 

all the virologic failures with maraviroc that were 

reported in the original study. 

In another analysis, the team applied the enhanced Trofile 

test to the screening specimens collected in this study. 30 The 

Lexus of the Trofile tests, the enhanced version has a 30-fold 

increase in sensitivity to detect minority variants. Fifteen

percent of the 721 participants entered into the study were 

found to have non-R5 virus at screening. If the participants 

with previously unrecognized non-R5 virus are 

excluded from the primary analysis, an identical 

68% of those in both arms get a viral load of less 

than 50 copies/mL at week 48. This makes sense 

and similar data were presented regarding the results 

of an ACTG study of vicriviroc (SCH 417690, SCH-D), 

another CCR5 antagonist. 31 

FIGURE 11 


Although it may seem that our cup runneth over when it 

comes to initial antiretroviral choices, clinicians are well 

aware that there are major limitations to the current crop 

of first-line drugs. Not every patient can or should take 

efavirenz and many do not tolerate ritonavir. Therefore, 

efavirenz and ritonavir-free regimens can be attractive. 


The STARTMRK data are impressive. Viral load responses 

for raltegravir were comparable with that of efavirenz and 

tolerability was better overall. The twice-daily dosing of 

raltegravir is a drag and further studies will determine if 

this agent, with its funky pharmacokinetic profile, can be 

administered once a day. A “New Drug Application” has 

been filed with the U.S. Food and Drug Administration 

for a treatment-naive indication for raltegravir and an 

outcome is expected in the summer of 2009. 

As for maraviroc, it’s unfortunate 

that one does not get a second 

chance to make a first impression. 

Many busy providers have it in 

their minds that this drug is not 

a contender for first-line status. 

However, the post hoc analyses 

from the MERIT trial may soften 

this stance and sway some. In 

addition, there has been an obvious 

and natural pull toward seeing 

maraviroc as an agent for earlier 

use in the course of the disease, 

when R5 tropism is more likely. 

In the absence of another large 

randomized trial, early use of 

maraviroc will depend on the faith of 

clinicians in this agent. Data aside, the 

test may be improved, but the cost of 

the Trofile assay remains decidedly 

unenhanced and far be it from me to 

waste another opportunity to signal 

displeasure with the pricing of this 

important clinical assay. 

In both drugs we find the potential to craft regimens for 

patients in difficult situations (e.g., drug intolerance or 

resistance). Use of these drugs in the treatment naive is 

inevitable. How tightly we embrace each agent over the 

coming year will be interesting to watch. ª


FIGURE 12 

Study Snapshot: STARTMRK 

Design: Randomized, double-blind, non-inferiority clinical trial of raltegravir vs. efavirenz, when taken with tenofovir/emtricitabine, 

among HIV-infected, treatment-naive patients. 

Population: 563 patients, randomized 1:1 to each treatment arm. Trial participants were mostly male and non-white. 

Main Results: At week 48, 86% of patients who had been randomized to raltegravir compared to 82% who had been assigned to efavirenz 

achieved a viral load < 50 copies/mL—a 4% difference meeting the condition for non-inferiority. CD4+ cell count gains were seen in both 

arms with a statistically significantly greater increase seen with raltegravir than efavirenz (189 cells/mm 3 vs. 163 cells/mm 3 , respectively). 

Significance: Viral load responses for raltegravir were comparable with that of efavirenz and tolerability was better overall. 

Further studies will determine if this agent can be administered once a day. A “New Drug Application” has been filed with the 

U.S. Food and Drug Administration for a treatment-naive indication for raltegravir and an outcome is expected this summer. 

Study Snapshot: MERIT 

Design: Randomized study comparing the efficacy of zidovudine/lamivudine plus either 600 mg efavirenz, 300 mg maraviroc 

once daily or 300 mg maraviroc twice daily in antiretroviral-naive patients. 

Population: 740 patients who were treatment-naive and harboring R5-only virus at screening. 

Main Results: At 48 weeks, 65.3% of the patients who were taking maraviroc had a viral load < 50 copies/mL vs. 69.3% of 

those who were treated with efavirenz (everyone got zidovudine/lamivudine). The difference was 4.2%, with a lower limit bounds 

of the 97.5% CI that just exceeded the outer bounds for non-inferiority of 10%. If those with dual/mixed virus detected during 

the study are excluded, the difference in the proportion with a viral load of < 50 copies/mL narrows between the arms. If the 

participants with previously unrecognized non-R5 virus are excluded from the primary analysis, an identical 68% of those in both 

arms get a viral load < 50 copies/mL at week 48. 

Significance: These post hoc analyses may soften the stance that this drug is not a contender for first-line status and sway some providers.

6 

Why A5164 Is Important 


Immediate vs deferred ART in the setting of acute AIDS-related 

opportunistic infection: final results of a randomized strategy 

trial, ACTG A5164. Andrew Zolopa, J. Andersen, L. Komarow, 

A. Sanchez, C. Suckow, I. Sanne, E. Hogg, W. Powderly, 

ACTG A5164 Study Team. In: Program and abstracts of the 

15th Conference on Retroviruses and Opportunistic Infections; 

February 3-6, 2008; Boston, Mass. Abstract 142. 

FIGURE 13 


At the hospital at which I work at the University 

of North Carolina, there had long been two 

types of infectious diseases specialists: 

those who prescribed antiretrovirals during 

hospitalization for an opportunistic infection (OI) and 

those who waited until after the acute treatment of the OI 

was completed. 

Strenuous arguments by each camp to convince 

the other to change their ways had been fruitless. 

Accusations (and occasionally food) were hurled, 

but the opposing parties remained steadfast in their 

convictions—the aggressive treaters cited the need for 

the recruitment of immune reconstitution to facilitate 

recovery and the opportunity to observe antiretroviral 

intolerance in an in-patient setting, while the delayers 

pointed to the risk of immune reconstitution syndromes 

and overlapping toxicities of OI and HIV therapies. 

And, in this state of perpetual equipoise things would 

have remained had it not been for the fact that someone 

did a study called ACTG study A5164. In this trial, 282 

people with AIDS and treatable OIs (tuberculosis was an 

exclusion criterion) or bacterial infections were randomized 

to start HIV therapy during the acute 

treatment of the OI (within 14 days of 

OI diagnosis and 48 hours of study 

entry) or defer treatment until after 

initial treatment of the OI. 32 

The most common conditions 

participants experienced were 

pneumocystis carinii pneumonia 

(PCP) (63%), cryptococcal 

meningitis (12%) and bacterial 

infections (12%). Participants had 

to be either treatment naive—not 

uncommon as many presenting with 

acute OIs were previously unaware 

of their HIV infection—or be off HIV 

therapy for the eight weeks prior to 

study entry; over 90% turned out to 

be treatment naive. 

Antiretroviral selection was up to the 

local clinician, but the ACTG provided


tenofovir/emtricitabine, stavudine (d4T, Zerit) 

and lopinavir/ritonavir gratis. Thus, 80% of 

participants received the boosted PI that was 

provided by the study. The median CD4+ cell 

count at study entry was 29 cells/mm 3 . 

This being an ACTG study, the primary 

endpoints were less than straightforward and 

were pithily stated to be: 

• to compare the percentage of trial 

participants in the immediate therapy arm 

versus the delayed therapy arm at 48 weeks, 

with respect to survival without AIDS 

progression, with an undetectable plasma 

HIV-1 viral load (< 50 copies/mL); 

• survival without AIDS progression with 

detectable plasma HIV-1 viral 

load (≥ 50 copies/mL); and 

• AIDS progression and/or death. 

FIGURE 14 

At 48 weeks, the immediate treatment group had a 

14.2% reduced rate of AIDS progression or death 

compared with the deferred treatment group 

(24.1%) (HR = 0.53; 99% CI, 0.25-1.09; P = .023). 

Importantly, there was no significant difference in the 

number of cases of immune reconstitution inflammatory 

syndrome (IRIS) between arms (10 in the immediate 

versus 13 in the deferred). However, 70% of patients with 

PCP received adjunctive corticosteroids and this could 

have blunted or prevented such reactions. 


This was a challenging study to design and implement 

and credit is due to the study team for their perseverance. 

The data they have provided to us vindicate their efforts 

and have changed practice. These results support the 

early application of HIV therapy during acute OIs and 

bacterial infections to shorten the period of vulnerability 

to life-threatening AIDS progression. Concerns for IRIS 

are justified, but these data indicate that the benefits of 

antiretrovirals trump the risk of immune reconstitution 

complications in the setting of these OIs. 

An important caveat is that tuberculosis was not included 

in the study, largely due to concerns regarding drugdrug 

interactions. However, the prevalent OIs that these 

participants endured are the ones that clinicians in the 

United States, at least, are most likely to encounter. 

Additional supportive data demonstrating the benefits of 

treating severely ill HIV-infected patients were presented 

at IAC in Mexico City this past summer and involved an 

examination of the impact of HIV treatment on survival 

during and after admission to intensive care units (ICUs) 

in Brazil. 33 HIV therapy did not reduce the ICU mortality 

of HIV-infected patients, but instead was associated with 

better survival at six months after release from the unit. 

Clinicians should take the A5164 results to heart and, 

if they are not already doing so, start treatment for HIV 

during acute OIs such as those represented in the trial. To 

delay HIV therapy without a good reason can increase the 

risk of death for the patient. 

At our shop in North Carolina, the A5164 results have 

created (mostly) harmony when it comes to treating HIV 

among our patients with acute OIs. That achievement 

alone qualifies a study as being tops. ª

Study Snapshot: A5164 


Design: Randomized, phase 4 strategy trial of giving HIV therapy during acute treatment of OI (within 14 days of OI diagnosis 

and 48 hours of study entry) vs. deferral of treatment until after initial treatment of OI. 

Population: 282 people with AIDS and treatable OIs (tuberculosis was an exclusion criterion) or bacterial infections. 

Main Results: At 48 weeks, the immediate treatment group had a 14.2% reduced rate of AIDS progression or death compared 

with the deferred treatment group (24.1%) (HR = 0.53; 99% CI, 0.25-1.09; P = .023). 

Significance: Supports the early application of HIV therapy during acute OIs and bacterial infections to shorten the period of 

vulnerability to life-threatening AIDS progression. Concerns for IRIS are justified, but these data indicate that the benefits of 

antiretrovirals trump the risk of immune reconstitution complications in the setting of these OIs.


7 

Opt-Out Testing at 

Last? 


Opt-out testing for human immunodeficiency virus 

in the United States: progress and challenges. 

John G. Bartlett, Bernard M. Branson, Kevin 

Fenton, Benjamin C. Hauschild, Veronica 

Miller, Kenneth H. Mayer. The Journal of the 

American Medical Association. August 27, 

2008;300(8):945-951. 

Opting out increases HIV testing in a large STI 

outpatient clinic. Titia Heijman, Ineke Stolte, 

Harold Thiesbrummel, Edwin van Leent, Roel 

Coutinho, Han Fennema, Maria Prins. Sexually 

Transmitted Infections. December 22, 2008. 

[Epub ahead of print] 

FIGURE 15 

HIV is often unwittingly transmitted by people 

who are unaware they are infected. Marks 

and colleagues at the CDC estimate that the 

approximately 25% of HIV-infected persons in 

the United States who are undiagnosed are responsible for 

at least half of all new infections. 34 

Efforts to increase HIV testing have had, overall, lackluster 

results and the resurgence in the incidence of HIV infection 

among men who have sex with men (MSM) has led to the 

recognition of the limitations of the domestic prevention 

program and sparked a renewed commitment to identify 

those who have remained under the HIV detection radar. 

A major display of this commitment was the issuance of 

recommendations by the CDC in 2006 to expand HIV 

screening by having the screening be done in a doctor’s 

office. 16 Taking a page from the playbook that led to the 

near extinction of maternal-to-child transmission of the virus 

in the United States, the CDC shifted the burden of HIV 

testing from the patients to the shoulders of their health 

care providers. 

The recommendations say that all patients who are 13 

to 64 years of age (64? Couldn’t they have just said 65 

years of age, except in Florida where it arguably should be

FIGURE 16 

75 years?) are to be offered an HIV test during a clinical 

visit and more frequently (left open to the clinician’s 

imagination) if they are at risk (also left open to the 

imagination, but should mean those who have sex with 

anyone but a trusted monogamous partner who has been 

demonstrated to be HIV uninfected). 

The assumption, generally valid, is that increased screening 

will identify those with HIV, allowing them to enter care and 

treatment early, thus improving their health while reducing 

their infectiousness and (hopefully) their risk behaviors. 

But wait, there’s more. The recommendations introduce 

the concept of opt-out testing. Tearing down the sanctity 

of the intensive pre-test and post-test counseling that 

was designed to make HIV testing confidential, but 

also made it a pain in the ass to order, opt-out testing 

entails the elimination of the written informed consent 

and long-winded spiel about antibody windows. Instead, 

it is a streamlined process that looks a lot like what is 

done when a clinician orders an important or sensitive 

lab test—you tell the patient you plan on doing the test 

and if they don’t have an objection, you check the box, 

hand them the slip and wait for the results to come back. 

Routine HIV testing was to become routine. 

Beautiful, except in some places it is against the law. 

So, the CDC recommendations have only caused a very 

slow change in practice. In a special communication 

in JAMA, John G. Bartlett and colleagues describe the 

barriers, legal and otherwise, to the implementation of 

opt-out testing for HIV across the United States. Among 

these barriers are perceptions that counseling acts as an 


effective prevention strategy, uneven insurance 

coverage for the testing, risk of stigmatization 

and discrimination following the diagnosis of 

HIV infection and the belief that risk-based 

testing is more effective. 35 The article deftly 

addresses these concerns and is a must-read 

for the unconvinced. 

While it is too early to tell if the CDC 

recommendations are having their intended effect 

in the United States, data from some quarters 

do demonstrate increased rates of HIV testing 

following the shift to opt-out testing paradigms. 

An elegant example comes from the Netherlands 

(always ahead of the curve, the Dutch are). HIV 

testing rates at a sexually transmitted infection 

clinic in Amsterdam that boasts of 25,000 new 

visits annually were examined before and after 

opt-out testing was introduced. 36 

In 2006, prior to the implementation of the new 

testing policy in January 2007, 1,534/4,024 (38%) 

MSM patients and 5,254/19,341 (27%) heterosexual 

patients did not test for HIV. In 2007, however, only 

12% (470/3,865) of MSM and 4% (837/21,305) of 

heterosexuals opted-out of HIV testing. The major 

reasons offered by patients as to why they opted out of 

testing included fear of the result, a low risk perception 

and being recently tested for HIV. 

The proportion of patients with a positive HIV 

test remained constant during both time periods 

(approximately 3.5% of MSM and about 0.25% of 

heterosexuals tested positive), meaning that with 

the increased numbers tested and unchanged 

infection rates, more people with HIV were 

detected with the change to opt-out testing. 

Similar results have been reported from another Dutch 

clinic 37 and one in London. 38 Closer to my home, in North 

Carolina, the state prison system saw rates of voluntary 

HIV testing on admission increase from under 60% in 

October 2008 to 83% the next month following the 

institution of opt-out testing on Nov. 1. 


The old system of opt-in testing does not work. An 

estimated 20,000 people a year are infected with HIV 

by those who do not know they carry the virus. Although 

an emphasis on clinics, emergency rooms and hospitals 

still misses groups at risk and broader initiatives will be 

required to reach those disenfranchised from medical 

care, health care settings are an obvious starting point to 

expand and simplify HIV screening.


The available opt-out testing data look promising and 

even the American College of Physicians (ACP) this past 

World AIDS Day issued a statement in support of the 

CDC guidelines. 39 

At this point, we as HIV health care providers must 

encourage our primary and urgent care colleagues 

to embrace broad HIV testing and work with them to 

facilitate such screening. There are myriad ways to assist, 

from speaking with directors of emergency rooms and 

educating primary care clinicians in order to convince 

them of the sanity of this approach, to serving as a referral 

specialist for patients diagnosed with HIV. Consider 

yourself deputized. ª 

Study Snapshot: Progress and Challenges of Implementing Opt-Out HIV 

Testing in the United States 

Design: Evaluation of the implementation of the CDC’s recommendations for opt-out HIV testing in the United States. 

Main Results: Concerns about the change include laws in some states that mandate signed consent and counseling, a 

perception that counseling is an effective prevention strategy, variability in payment coverage for the test, concerns about the 

stigma and discrimination that may accompany the HIV diagnosis, and the possibility that other testing policies would be more 

effective. Eleven of 16 states have changed legislation to reduce barriers to testing, 35 of 74 national professional societies have 

endorsed the new recommendations, and multiple demonstration projects have shown feasibility. Metrics to evaluate the health 

outcomes have been defined, but the data necessary to determine the effects on early entry into care, the actual reduction in 

disease incidence, and the unanticipated consequences are not yet available. 

Significance: Increased screening will identify those with HIV, allowing them to enter care and treatment early, thus improving 

their health while reducing their infectiousness and (hopefully) their risk behaviors. Opt-out testing is a streamlined process that 

allows routine HIV testing to become routine. 

Study Snapshot: Opt-Out Testing at a Large Outpatient Clinic in Amsterdam 

Design: Evaluation of the effect of the new opt-out policy on uptake of HIV testing and positivity rate and identified factors 

associated with actively declining the HIV test. 

Population: Patients who presented for HIV testing at the STI outpatient clinic in Amsterdam, The Netherlands, (average of 

24,000 consultations/year) in 2006 and 2007. 

Main Results: In 2006, prior to the implementation of the new testing policy in January 2007, 1,534/4,024 (38%) MSM patients 

and 5,254/19,341 (27%) heterosexual patients did not test for HIV. In 2007, however, only 12% (470/3,865) of MSM and 4% 

(837/21,305) of heterosexuals opted-out of HIV testing. The proportion of patients with a positive HIV test remained constant 

during both time periods (~3.5% of MSM and ~0.25% of heterosexuals tested positive), meaning that with the increased 

numbers tested and unchanged infection rates, more people with HIV were detected with the change to opt-out testing. 

Significance: Increased screening will identify those with HIV, allowing them to enter care and treatment early, thus improving 

their health while reducing their infectiousness and (hopefully) their risk behaviors. Opt-out testing is a streamlined process that 

allows routine HIV testing to become routine.

8 

Updated U.S. HIV 

Incidence 


Estimation of HIV incidence in the United States. H. 

Irene Hall, Ruiguang Song, Philip Rhodes, Joseph 

Prejean, Qian An, Lisa M. Lee, John Karon, Ron 

Brookmeyer, Edward H. Kaplan, Matthew T. McKenna, 

Robert S. Janssen, for the HIV Incidence Surveillance 

Group. The Journal of the American Medical 

Association. August 6, 2008;300(5):520-529. 

FIGURE 17 


T 

his year the CDC revised its estimate of how 

many people in the United States are infected 

with HIV. 40 Previous estimates of 40,000 cases 

per year relied on back calculation, based on 

incident AIDS case reporting data and the probability 

of the incubation period of the virus from the moment of 

infection to the time of diagnosis of AIDS. 

There clearly have been limitations to this approach. The 

estimation of the duration of HIV infection has become 

increasingly difficult to pin down given the widespread 

use of potent HIV therapies. Further, the data used to 

derive the incidence estimates were often dated. 

To readdress, as well as redress, the annual incidence 

estimate, the CDC devised a new system that 

incorporates HIV incidence data from 22 states reporting 

HIV infections and an analysis of leftover blood from HIV 

testing specimens that searches for patterns of recent 

HIV infection in those who were HIV seropositive. 16 The 

latter relies on the use of the BED HIV-1 capture enzyme 

immunoassay, which can distinguish recent infections of


approximately 150 days or less from more chronic 

infection. 

Specifically, the test looks at anti-HIV IgG 

(immunoglobulin G) levels compared to total 

IgG concentrations as it has been observed that 

anti-HIV antibodies increase relative to the total 

immunoglobulin level soon after acquisition of the 

virus. The combination of standard and BED testing 

is known as the serologic testing algorithm for 

recent HIV seroconversion (STARHS). 

In 2006, an estimated 39,400 people were 

diagnosed with HIV infection in the 22 

reporting states. Of the 6,864 HIV-seropositive 

specimens tested with the BED assay, 

31% were classified as recent infections. 

Extrapolating these data to the nation as a 

whole resulted in a new annual HIV incidence 

of 56,300 (95% CI, 48,200-64,500). 

This is a 40% increase from the previous estimates. 

Some have incorrectly misconstrued these results 

to mean there has been a 40% increase in the 

incidence of HIV—a misconception that should be 

corrected with an explanation that the analysis used 

a new method to estimate HIV incidence and found 

that prior estimates had been inaccurately low. In 

fact, overall HIV incidence has been relatively stable 

over the past few years, according to this report. 

FIGURE 18 

Over half of the new infections were among MSM and 45% 

were among black individuals. Using a model of extended 

back-calculation, the investigators estimated the number of 

new infections from 1977 to 2006. The result was a picture 

of the domestic epidemic with a peak in incidence in the 

mid 1980s followed by a decline and smaller rise in the late 

1990s. 

There were notable differences in trends of HIV incidence by 

race and risk category. MSM were the predominant group 

of infected persons early in the epidemic, but by 1988 to 

1989 the incidence in this population dropped below that of 

injection drug users (IDUs). 

However, since 1990, HIV incidence among MSM has 

progressively increased. A disproportionate number of new 

infections have occurred among blacks; the incidence in 

this group climbed during the first decade of the epidemic 

and has remained fairly stable over the past several years. 

Incidence trends among women have also been largely 

unchanged in recent years. 


The revised HIV incidence data paint a vivid and detailed 

picture of the epidemic in the United States and likely 

present a more accurate estimate of how many people 

acquire the virus. While the adjustment in the number of 

new cases upward by approximately 40% was surprising, 

the finding that HIV remains concentrated among MSM and 

blacks is not. 

The rise, fall and resurgence 

of HIV among MSM is striking. 

Data from the National HIV 

Behavioral Surveillance (NHBS) 

System point to an alarming 

increase in HIV acquisition 

among MSM between 13 to 24 

years of age, 41 demonstrating 

that official and grassroots 

prevention messages are not 

adequately reaching or being 

received by this group of men. 

Likewise, the increased 

burden of HIV among African 

Americans can only invoke 

sadness. The Black AIDS 

Institute made the disturbing 

observation that if their 

numbers made up a separate 

country, HIV-infected African 

Americans would rank 16th in 

the world in HIV prevalence. 42

The progressive concentration of HIV/AIDS among 

African Americans is disturbing and shameful. These 

trends have served as a wake-up call to affected 

communities and their leaders to the danger in their midst. 

The CDC report has led to the expected calls for 

increases in funding to expand prevention efforts. 

However, there remains debate as to which interventions 

are most effective and feasible, especially for the 

populations that are most at risk. Unfortunately, an HIV 

vaccine is not in the offing and neither is a marketable 

topical microbicide. 

An alternative approach is to further initiatives to find, 

counsel and treat those with HIV infection. As described 

above, our ability to identify those who are unknowingly 

infected has been dismal. 


With some models finding that a lion’s share of new 

infections may be acquired from individuals with acute 

HIV infection, our failure to detect chronic infection may 

well be compounded by our inability to find those more 

recently infected. Enhanced detection—whether via 

routine HIV testing, algorithms for uncovering acute HIV 

among those screened for HIV and/or outreach—is a 

start. A diagnosis of HIV infection itself may or may not 

lead to behavioral change that will then reduce the risk of 

transmission—the data have been mixed—however, the 

identification of HIV infection also provides an opportunity 

to counsel and treat, potentially reducing viral load and 

infectiousness. Numbers matter and as the mantra of 

40,000 new cases of HIV is superseded by a frighteningly 

higher figure, we can only hope that the attention the new 

estimates bring is accompanied by action. Otherwise, we 

will continue to be sad witnesses to a slaughter. ª 

Study Snapshot: Estimation of HIV Incidence in the United States 

Design: Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 

in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. 

Information on HIV cases was reported to the CDC through June 2007. Incidence of HIV in the 22 states during 2006 was 

estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results 

were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS 

incidence from 50 states and the District of Columbia. 

Main Results: In 2006, an estimated 39,400 people were diagnosed with HIV infection in the 22 reporting states. Of the 6,864 

HIV-infected patients tested with the BED assay, 31% were classified as recent infections. Extrapolating these data to the 

nation as a whole resulted in a new annual HIV incidence of 56,300 (95% CI, 48,200-64,500). This is a 40% increase from the 

previous estimates. 

Significance: The revised HIV incidence data paint a vivid and detailed picture of the epidemic in the United States and likely 

present a more accurate estimate of how many people acquire the virus.


9 

Survival in the Time 

of HAART 


Reduction in AIDS defining events/death 

(ADE/D) with etravirine (ETR) compared to 

placebo (PL): pooled DUET 48 week results. 

R. Haubrich, J. Eron, M. Thompson, P. Reiss, 

R. Weber, M. Peeters, R. van Solingen-Ristea, 

G. Beets, E. Voorspoels, G. de Smedt. In: 

Program and abstracts of the 48th Annual 

ICAAC/IDSA 46th Annual Meeting; October 

25-28, 2008; Washington, D.C. Abstract 

H-1239. 

AIDS defining conditions (ADCs) in the 

BENCHMRK -1 and -2 trials: 48 week 

analysis. J. E. Eron, B. Y. Nguyen, R. T. 

Steigbigel, D. A. Cooper, R. R. Rhodes, A. 

Meibohm, J. Zhao, R. Isaacs, H. Teppler. In: 

Program and abstracts of the 48th Annual 

ICAAC/IDSA 46th Annual Meeting; October 

25-28, 2008; Washington, D.C. Abstract 

H-1249. 

It was really not that long ago, before the newfangled 

PCR (polymerase chain reaction) assays, when we 

relied on hard clinical endpoints for HIV treatment trials 

and were suspicious of surrogate markers of these 

outcomes. (Anyone remember p24 antigen, neopterin or 

beta-2-microglobulin?) After John Mellors from the University 

of Pittsburgh Medical Center preached the righteousness of 

the HIV viral load assays as oracles of disease progression 

and with the steep declines in AIDS and death among study 

participants, we responded with a hearty “hallelujah.” 43 

Nowadays, when the vast majority of treated patients do very 

well (Garrison Keillor might even say they all do better than 

average), small differences in viral load responses can make 

or break an antiretroviral. 

So, are clinical outcomes in HIV clinical trials dead, killed 

at the hands of HAART? Not entirely. The potency of 

combination antiretroviral regimens has slowed the pace 

of HIV disease progression to a crawl, but for patients who 

have advanced immunodeficiency and who are at risk for 

imminent opportunistic complications, HIV therapy can 

reverse the nosedive and avoid a crash. 

The Lazarus-like ability of HAART is illustrated nicely with 

the findings from two major recent clinical antiretroviral 

treatment trials. The design and main results of the DUET and 

BENCHMRK trials have been previously reported on The Body 

PRO. Both trials enrolled treatment-experienced patients. 44-46 

DUET: Etravirine 

For DUET, eligible patients were required to have at least one 

NNRTI and three or more primary PI mutations. All patients 

received an optimized regimen that included ritonavir-boosted 

darunavir (TMC114, Prezista) and half the patients were 

randomized to have etravirine (TMC125, Intelence) added. 

In a secondary analysis of the DUET trials, the 

addition of etravirine led to greater rates of virologic 

response over 96 weeks, but also reduced progression 

to an AIDS-defining condition or death—with less 

than 6% of the etravirine-assigned participants 

developing these clinical endpoints, compared to 

about 10% of the patients who were randomized to 

placebo (P = .04). 47

FIGURE 19 

Similarly, at one year, the rates of hospitalization and total 

days spent in a hospital were significantly different across 

the treatment arms: 23% of placebo participants were 

inpatients, versus 17.5% of the etravirine participants—a 

result that was significant even after adjusting for baseline 

viral load, CD4+ cell count and enfuvirtide (T-20, Fuzeon) 

FIGURE 20 


use (P = .0006). Furthermore, 

over the first year of the 

trial, etravirine-receiving 

participants had almost 1,000 

fewer days of hospitalization 

than the control participants 

(1,702 versus 2,747 days, P = 

.0195). 

BENCHMRK: Raltegravir 

In BENCHMRK, participants had 

triple-class (NRTI, NNRTI and PI) 

resistance and were randomized 

to raltegravir or placebo in 

addition to an optimized regimen. 

Given the entry criteria, it is 

not surprising that the entry 

CD4+ cell counts in these 

studies were generally low 

(approximately 100 cells/mm 3 

and about 150 cells/mm 3 , 

respectively). 

The clinical outcome data from 

the BENCHMRK studies, which placed raltegravir on the 

map as a potent agent for treatment-experienced patients, 

tell the same story. 48 Treatment with raltegravir tended 

to reduce the rate of the development of an AIDSdefining 

condition or death by about half. Overall, rates 

of clinical outcomes were low—only 37 participants had a new 

AIDS-defining illness or died. 

Interestingly, patients who 

experienced these outcomes 

had lower CD4+ cell counts 

at baseline (less than 10 cells/ 

mm 3 ) and almost all had a prior 

AIDS-related diagnosis. 


These trials demonstrate an 

actual clinical benefit of these 

regimens beyond improvements 

in CD4+ cell count and viral 

load. Fewer people got sick and 

died if they received the active 

study agents. Such results are a 

testament to the ability of these 

medications, in combination with 

others, to reverse the ravages of 

HIV disease. They also indicate 

that such therapies are best 

applied before they become too 

little, too late.


One of the most exciting developments in HIV 

care over the past couple of years has been 

the new opportunities for treating our most 

treatment-experienced and ill HIV-infected 

patients. Bridges were burned, along with 

entire drug classes, but the new drugs have 

given some a new lease on life. That it has made 

a difference is clinically evident and these data 

provide a resounding “truth that” to our experience. 

Unfortunately, it is likely we will continue to need 

last-ditch drugs even as we try to diagnose 

patients earlier in the course of their HIV disease. 

The chaos, mental illness and other challenges 

in the lives of our patients ensure that adherence 

will be an ongoing problem and that the pipeline 

will need to continue to supply us with drugs to 

suppress resistant virus. Such drugs are a safety 

net for the all too many who are precariously 

balanced on the precipice between maintaining 

their health and catastrophe. If we cannot stop 

them from falling, we can at least catch them. ª 

FIGURE 21 

Study Snapshot: AIDS-Defining Events/Death (ADE/D) in DUET Studies 

Design: Two international, randomized, double-blind studies evaluating the efficacy and safety of etravirine vs. placebo, each 

given with a background regimen of darunavir + ritonavir, investigator-selected NRTI(s) and optional enfuvirtide. 

Population: 1,203 patients who experienced virologic failure on stable antiretroviral therapy with documented NNRTI resistance, 

a viral load > 5,000 copies/mL and at least three primary PI mutations. 

Main Results: Addition of etravirine led to greater rates of virologic response over 96 weeks, but also reduced progression to an AIDSdefining 

condition or death—less than 6% of the etravirine-assigned participants developing these clinical endpoints, compared to 

about 10% of the patients who were randomized to placebo (P = .04). Furthermore, over the first year of the trial, etravirine-receiving 

participants had almost 1,000 fewer days of hospitalization than the control participants (1,702 vs. 2,747 days, P = .0195). 

Significance: Demonstrate an actual clinical benefit beyond improvements in CD4+ cell count and viral load. Fewer people got 

sick and died if they received the active study agents. Testament to the ability of these medications, in combination with others, 

to reverse the ravages of HIV disease. Also indicate that such therapies are best applied before they become too little, too late. 

Study Snapshot: AIDS-Defining Conditions (ADCs) in BENCHMRK-1 and -2 

Design: Multicenter, randomized, triple-blind studies evaluating the safety and efficacy of raltegravir 400 mg twice daily vs. 

placebo, each taken with optimized background therapy. 

Population: 699 HIV-infected patients failing HAART with resistance to at least one agent in NNRTI, NRTI and PI classes. 

BENCHMRK-1 enrolled 350 patients in Europe, Asia, the Pacific and Peru. BENCHMRK-2 enrolled 349 patients in North America. 

Main Results: Treatment with raltegravir tended to reduce the rate of the development of an AIDS-defining condition or death by about half. 

Significance: Demonstrate an actual clinical benefit beyond improvements in CD4+ cell count and viral load. Fewer people got 

sick and died if they received the active study agents. Testament to the ability of these medications, in combination with others, 

to reverse the ravages of HIV disease. Also indicate that such therapies are best applied before they become too little, too late.

10 

No Bones About It 


Fracture prevalence among human immunodeficiency 

virus (HIV)-infected versus non-HIV-infected patients 

in a large U.S. 

healthcare system. FIGURE 22 

Virginia A. Triant, 

Todd T. Brown, 

Hang Lee, Steven 

K. Grinspoon. The 

Journal of Clinical 

Endocrinology 

and Metabolism. 

September 

2008;93(9):3499- 

3504. 

Continuous 

antiretroviral therapy 

(ART) decreases 

bone mineral 

density: results from 

the SMART study. B. 

Grund, A. Carr, The 

Insight Smart Study 

Group. In: Program 

and abstracts of the 

48th Annual ICAAC/ 

IDSA 46th Annual 

Meeting; October 

25-28, 2008; 

Washington, D.C. 

Abstract H-2312a. 


Maybe the SMART study was aptly named 

after all. The trial was designed to determine 

whether a strategy of limiting patients’ 

exposure to antiretrovirals would reduce 

adverse events such as CVD, hepatic, renal and other 

complications associated with HIV therapies. Famously, 

the investigators found that these medications were 

protective against such conditions. 12 However, when 

it comes to bone health, the investigators were on to 

something. 

By way of background, low bone mineral density (BMD) 

has been found to be extremely prevalent among those 

with HIV infection. Clinical cohort data suggested that as 

many as 60% to 70% of HIV-infected patients have BMD 

levels that qualify as osteopenia, with a much lower 5% 

to10% having frank osteoporosis. 49,50


FIGURE 23 

In the general population, the lower the BMD, 

the greater the risk for fracture. Therefore, there 

has been concern regarding just how much HIV 

therapies are contributing to BMD reductions and 

how much those living with HIV infection are at risk 

for fracture. 

However, the observational data that have 

been gathered until now do not exactly point to 

antiretrovirals as a bone leeching smoking gun. 

HIV-infected patients often have other risk factors for 

reduced BMD; this includes such things as smoking, 

prior significant weight loss, corticosteroid use and 

hypogonadism. These factors have been thought to 

explain much of the osteopenia and osteoporosis 

among this population, a position supported by BMD 

data among treatment-naive patients entering into 

clinical trials, where higher than expected rates of 

osteopenia were observed. 51 However, those same 

clinical trials demonstrated that BMD can fall further 

after the start of antiretroviral therapy, especially with 

regimens containing tenofovir. 

With an enhanced appreciation for the challenges 

facing HIV-infected patients as they age, attention 

to bone health has increased. Already there are 

indicators of potential trouble ahead. A recent study 

of patients enrolled in a multi-hospital patient registry 

in Boston found the rate of fractures to be higher 

among patients with HIV infection compared to those 

without known HIV. 52 

Among the more than 8,500 patients with 

HIV infection, the prevalence of fractures of 

the wrist, hip and vertebrae was 2.87 

patients per 100 persons compared 

with 1.77 per 100 persons for the over 

2 million controls (P < .0001). The risk 

of fracture was greater for HIV-infected 

patients regardless of gender. 

Overall, fracture rates were higher among 

HIV-infected persons at each of the three 

anatomical sites studied (wrist, hip and 

vertebrae), as were combination fractures, 

although among women rates of hip fractures 

were not significantly different by HIV status. 

However, this and other studies have 

left unanswered the question of whether 

antiretrovirals play a major role in BMD loss. 

The randomized SMART study design is ideal 

for exploring this very question. DEXA (dual 

energy X-ray absorptiometry) scans were 

performed as part of a body composition 

substudy along with quantitative computed tomography 

(qCT) scans that can measure the density of trabecular 

bone. Of the 275 substudy participants enrolled, 214 had 

follow-up BMD determinations (116 in the intermittent 

antiretroviral therapy arm and 98 in the continuous therapy 

arm). 

Importantly, BMD declined in both SMART study 

groups. However, those randomized to defer or 

interrupt HIV therapy experienced less of a drop than 

those who maintained antiretroviral treatment. 53 The 

estimated differences in mean BMD change from 

baseline through follow-up were 1.4% (P = .002) at the 

hip by DEXA, 2.9% (P = .01) for spine by qCT and 

1.2% (P = .05) for spine by DEXA—all favoring drug 

interruption/deferral. As more individuals in the treatment 

interruption arm take up HIV treatment, these results may be 

underestimating the impact of antiretroviral therapy on BMD 

over time. 

Specific antiretrovirals were not associated with loss 

of BMD (56 of the 98 participants on NRTIs received 

tenofovir), but curiously, neither were traditional risk factors 

for osteopenia. 

The investigators also examined the rate of fractures in the 

entire SMART trial cohort of 5,472 participants (providing for 

approximately 7,500 person-years of follow-up per group). 

Ten of 2,753 participants in the continuous HIV therapy group 

(rate 0.13 per 100 person-years) and two of 2,720 in the drug 

interruption/deferral group (rate 0.03 per 100 person-years) 

experienced significant fractures (hazard ratio for continuous 

versus interruption = 4.9; 95% CI, 1.1-22.5; P = .04).


BMD, like so many parts of our bodies, drops as we age. 

An accumulation of data points toward a heightened 

risk of significant osteopenia and osteoporosis over time 

for people living with HIV infection. The calculus of this 

problem is obvious: More people with HIV infection are 

living long lives and their risk of fracture increases with 

time. 

Yet, we have no comprehensive approach to the 

prevention and management of reduced BMD among 

HIV-infected patients. DEXA scans to screen for low 

BMD are not a routine part of the clinical management 

of HIV disease and, when they are ordered, may incur 

insurance company wrath. 

Part of the problem has been a lack of clarity regarding 

who to screen. However, the observational study data 

are fairly consistent in their finding that patients who are 

Caucasian, are older, have a low BMI (bone mass index) 

and have a low nadir CD4+ cell count are at increased 

risk of reduced BMD. Additional factors to consider 

include a history of corticosteroid use, smoking, alcohol 

abuse, sedentary lifestyle and, of course, a history of a 

traumatic fracture. Screening of postmenopausal women 

should follow guidelines established for the general 

population (see www.nof.org/physguide). 

For patients who are found to have BMD levels 

that sufficiently increase the risk of fracture, 

we do know that bisphosphonates work. An 

ACTG trial demonstrated nicely that alendronate 

(Fosamax) taken with vitamin D and calcium is 

effective in both men and women in increasing 

bone density. 54 Clinicians encountering reduced 

BMD need to become well versed in the workup 

of secondary causes of osteopenia and 

osteoporosis, which include vitamin D deficiency, 

parathyroid disease and thyroid diseases. 55 

Beyond the risk of low BMD that accompanies 

aging and the lifestyle factors that are more 

common in HIV-infected patients, the SMART 

study results suggest HIV therapies also kick 

bone density down the hill. This is an important 

finding and these data are the clearest to 

FIGURE 24 


implicate potent HIV treatment in bone loss. The mechanism 

for such an effect is not known and additional information 

from this study is likely forthcoming. Whether there are 

differences between types of antiretroviral regimens and 

specific host factors that interact with HIV therapies need to 

be explored in other studies. Meanwhile, the SMART BMD 

finding suggests that our surveillance for BMD problems 

should be stepped up for those on HIV therapy. 

Clearly, fractures of the axial skeleton are a major cause of 

morbidity and can lead to permanent disability; therefore, 

this is an issue that, with the inevitable rise in cases and 

the accompanying fear, will only grow larger. Already, 

motivated by community concerns and calls to action, 

the ACTG has established a working group to develop 

proposals related to bone health. But the research has 

to be matched by efforts to educate clinicians and their 

patients regarding the risks for low BMD. This is a role 

for our representative organizations, with assistance from 

relevant endocrinology groups. 

In addition, guidelines for the use of DEXA need to be 

developed based on a re-evaluation of the data that have 

emerged over the past few years. 2009 can be the year 

we start to take bone health among HIV-infected persons 

seriously. ª


Study Snapshot: Fracture Prevalence in a Large U.S. Health Care System 

Design: Population-based study between October 1, 1996 and March 21, 2008. 

Population: A total of 8,525 HIV-infected and 2,208,792 HIV-uninfected patients with at least one inpatient or outpatient 

encounter. 

Main Results: Among the patients with HIV infection, the prevalence of fractures of the wrist, hip and vertebrae was 2.87 

patients per 100 persons compared with 1.77 per 100 HIV-uninfected persons (P < .0001). The risk of fracture was greater for 

HIV-infected patients regardless of gender. 

Significance: BMD, like so many parts of our bodies, drops as we age. An accumulation of data points toward a heightened 

risk of significant osteopenia and osteoporosis over time for people living with HIV infection. Shows need for comprehensive 

approach to the prevention and management of reduced BMD among HIV-infected patients. 

Study Snapshot: Bone Mineral Density in SMART Study 

Design: Randomized substudy of SMART cohort designed to determine whether a strategy of limiting patients’ exposure to 

antiretrovirals would reduce adverse events such as CVD, hepatic, renal and other complications associated with HIV therapies. 

Population: 275 substudy participants, 214 had follow-up BMD determinations (116 in the intermittent antiretroviral therapy arm 

and 98 in the continuous therapy arm). Also examined the rate of fractures in the entire SMART trial cohort of 5,472 participants 

(providing for approximately 7,500 person-years of follow-up per group). 

Main Results: BMD declined in both SMART study groups. However, those randomized to defer or interrupt HIV therapy 

experienced less of a drop than those who maintained antiretroviral treatment. The estimated differences in mean BMD change 

from baseline through follow-up were 1.4% (P = .002) at the hip by DEXA, 2.9% (P = .01) for spine by qCT and 1.2% (P = .05) 

for spine by DEXA—all favoring drug interruption/deferral. 

Significance: Beyond the risk of low BMD that accompanies aging and the lifestyle factors that are more common in HIVinfected 

patients, the results suggest HIV therapies also kick bone density down the hill. Suggests that our surveillance for 

BMD problems should be stepped up for those on HIV therapy. The mechanism for such an effect is not known and additional 

information from this study is likely forthcoming.


Obama Wins! 


If the last eight years have taught us anything it is that 

we can no longer underestimate the influence of the 

occupant of the Oval Office on our lives—a lesson 

one can only hope the followers of Ralph Nader have 

belatedly absorbed. When it comes to responding to the 

HIV pandemic, we have seen that the U.S. president can 

have a considerable impact. 

Of the outgoing chief executive one must acknowledge 

his willingness to actually speak about HIV/AIDS and to 

pump millions into funding for antiretrovirals in developing 

countries. No matter how one rates George W. Bush and 

his troubled tenure, it is unassailable that there is not a 

small number of people (estimates are 1.7 million) who 

received effective HIV therapies through his President’s 

Emergency Plan for AIDS Relief (PEPFAR). 

Certainly, there were strings attached. There were 

restrictions. Sex workers and intravenous drug users 

were often left out and there had been a narrow-minded 

emphasis on abstinence to prevent HIV transmission. 

Furthermore, although billions of dollars have been 

spent on the program, U.S. aid to developing countries 

is criticized as being miserly compared to other wealthy 

nations when looked at as a proportion of GDP (gross 

domestic product). Overall, it will be difficult to view the 

merits of PEPFAR without looking through the lens of the 

presidency of the man who initiated the fund. 

Domestically, there were markedly less tangible 

achievements when it comes to confronting HIV. 

Protecting tens of thousands of Americans against this 

lethal virus took a backseat to the theoretical threat of a 

dirty bomb or another type of terror attack. Infection rates 

went unchanged, HIV-infected individuals continued to 

be diagnosed late in their disease and many had trouble 

paying for their medications and medical care. 

As President Barack Obama takes command, we look 

to him to right the long list of wrongs. With an evolving 

economic meltdown well underway, wars being waged 

and who knows what next crisis to emerge, we can be 

forgiven for wondering whether there is any room on the 

famous BlackBerry for a to-do list that includes “provide 

HIV medications for all and enhance funding for research 

to prevent, treat and cure HIV.”


But one can hope, and hope is what this president is all about. 

• We hope to see the spending of more money to save the 

lives of those in the United States instead of funding conflicts 

that end the lives of people living in other countries. 

• We hope to see a domestic AIDS initiative that will 

recognize the shameful failures of our current health 

system and that supports the expansion of HIV testing 

and treatment. 

• We hope to see PEPFAR realize its full potential by 

embracing effective prevention strategies, as has been 

recommended by the Institute of Medicine. 

It is by now hackneyed to say but nonetheless true that we 

hope to see change. One can hope that our 44th president, 

inheriting from the 43rd challenges he could have scarcely 

imagined when he decided to run for this office, will be 

able to steer a course that continues to recognize our 

commitment to combating HIV abroad, but also appreciates 

the threat that HIV is to our homeland. As those who care for 

people living with HIV, we can hope for these changes (and 

help, and advocate, and contribute and lead). ª


Financial Crisis 

Hurts People 

Living With HIV 


There is no doubt that the current recession/ 

depression we are experiencing will hurt people 

living with HIV infection. What Medicare Part D 

started, the economic crisis will finish. HIV-infected 

people will lose their jobs and with them their health insurance. 

Those middle-class patients with coverage will see their 

medical benefits reduced and their out-of-pocket costs for 

medications and care increased. Some HIV-infected people 

have already stopped their medications due to an inability 

to afford prescription co-pays. Others have had to change 

antiretrovirals. 

A diligent, hard-working and absolutely lovely patient of 

mine with a long-standing undetectable viral load while 

on efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC, 

Atripla)—and with medical insurance!—had to change to 

zidovudine/lamivudine plus efavirenz to take advantage 

of a pharma-sponsored co-pay program and reduce his 

monthly medication cost from $500 to $200. When gas 

prices rise again, and they will, we will again see people 

missing routine office visits because they cannot afford 

to fill their tanks. 

This will be a tough year for many people living with HIV 

infection. As clinicians, we will be tasked with trying 

to fill the gaps of a system that will allow many of our 

patients to fall further into debt or the throes of AIDS. 

Every single HIV regimen that is stopped for reasons 

that are financial rather than medical, every dose that is 

skipped by patients trying to ration their antiretrovirals, 

every missed clinic visit by patients tired of getting 

collection notices, every emergency room visit by 

those who had no other option—every one of these 

failures turns back the clock on our efforts to control 

this epidemic and demands protest. Silence is not 

an option and silence is not what we will expect from 

our professional organizations or those who claim to 

advocate for people living with HIV. ª



Jesse Helms’ U.S. 

Travel Ban Lifted 

Go ahead and pinch yourself. The travel ban 

against people from other nations entering 

or immigrating to the United States has been 

finally lifted. Tucked into the reauthorization 

of PEPFAR, the change was sponsored by Senators 

John Kerry (D-Massachusetts) and Gordon Smith 

(R-Oregon), more than 20 years after North Carolina 

Senator Jesse Helms (R-another planet) first proposed 

the ban. 

The lifting of this ridiculous restriction is a victory of 

the rational and compassionate over the intolerant and 

punitive. It is a correction that those of us in the United 

States should be proud of, even as we are shamed by 

the original mistake. Now, all that remains is for the lifting 

of the ban to be implemented—another item on the long 

to-do list of our new administration. ª


A Diehard AIDS 

Denialist Dies 


My daughter was 2 years old in 2001 when I 

saw the cover of Mothering magazine with 

a very pregnant Christine Maggiore proudly 

showcasing her belly adorned with a bright 

red circle and slash across the letters AZT. As an HIV 

clinician, researcher and father, I was shocked by the 

utter denial implicit in the pose and by the publishers for 

promulgating such a deadly and patently wrong message. 

It was the last issue we bought, but my first introduction 

to this unrepentant firebrand who, although HIV infected 

and once an AIDS service organization volunteer, came 

to deny that the HIV coursing through her body was the 

cause of AIDS. 

Despite the development of the HIV RNA assay, which 

detected the presence of the actual AIDS virus and 

reliably predicted prognosis, as well as her own 3-yearold 

daughter’s death from PCP (a diagnosis she and her 

husband contested), Maggiore was unwavering in her HIV 

denialism and refused to take HIV medications. 

She founded the Alive & Well AIDS Alternatives organization 

as a platform to question the accuracy of HIV science. 

Fatefully, she would meet with South African President Thabo 

Mbeki who came to espouse similar views questioning the 

link between HIV and AIDS and tragically stalled his country’s 

efforts to provide HIV medications to its people. According 

to one recent study, more than 330,000 lives were lost as a 

consequence of Mbeki’s failure to accept the preponderance 

of scientific evidence and implement an antiretroviral 

treatment program in South Africa. 56 

Maggiore died of pneumonia in December 2008 at age 

52. The exact cause of her death has yet to be reported 

and predictably, her colleagues—always proficient in 

denial—state her death was not related to HIV. 

Skepticism can be healthy, but a refusal to face the 

difficult reality that there exists a virus that is often 

transmitted during an act of love and that slowly destroys 

our immune system to the point of leaving us defenseless 

is not. In fact, as Maggiore proved, it can be deadly. 

Unfortunately, her death doesn’t end this fringe movement. 

Others like her remain, unconscionably volunteering their 

recommendations to vulnerable patients who are afraid of 

medications. ª


Wrap-Up 

What a year! My love of what I do for a living 

is emotionally fueled by my relationship 

with my patients, but is intellectually 

powered by the rush that comes with 

discovery. Just as the virus we confront replicates at 

rates that challenge comprehension, we also must 

constantly grow and shift our own knowledge of how 

HIV ticks. In this virus versus human race, we learn and 

unlearn, err and correct, reaching in all directions for the 

small or large breakthrough. The list above includes a 

selection of the stories that have the greatest potential, 

in my view, of changing how we think and, ultimately, 

what we do. And changing what we do, for the better, is 

what our search for answers is all about. ª

References 

1. 

2. 

3. 

4. 

5. 

6. 

7. 

8. 

9. 

10. 


May M, Sterne JAC, Sabin C, et al, for The Antiretroviral Therapy (ART) Cohort Collaboration. Prognosis of HIV-1-infected 

patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. May 31, 

2007;21(9):1185-1197. 

Weber R, Sabin CA, Friis-Møller N, et al, for The Data Collection on Adverse Events of Anti-HIV Drugs Study Group. Liver-related 

deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. August 14/28, 

2006;166(15):1632-1641. 

Phillips AN, Gazzard B, Gilson R, et al, for The UK Collaborative HIV Cohort (CHIC) Study Steering Committee. Rate of 

AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AIDS. August 20, 

2007;21(13):1717-1721. 

Smit C, Geskus R, Walker S, et al, for CASCADE Collaboration. Effective therapy has altered the spectrum of cause-specific 

mortality following HIV seroconversion. AIDS. March 21, 2006;20(5):741-749. 

Lau B, Gange SJ, Moore RD. Risk of non-AIDS-related mortality may exceed risk of AIDS-related mortality among 

individuals enrolling into care with CD4+ counts greater than 200 cells/mm3 . J Acquir Immune Defic Syndr. February 

1, 2007;44(2):179-187. 

Monforte A, Abrams D, Pradier C, et al, for The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study 

Group. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 

October 18, 2008;22(16):2143-2153. 

Marin B, Thiébaut R, Rondeau V, et al, and CASCADE Study Group. Association between CD4 and HIV RNA with non-AIDS-related 

causes of death in the era of combination antiretroviral therapy (cART). In: Program and abstracts of the 4th International AIDS Society 

Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB019. 

Bruyand M, Thiebaut R, Lawson-Ayayi S, et al, and Groupe d’Epidémiologie Clinique du SIDA en Aquitaine (GECSA). 

Immunodeficiency and risk of AIDS-defining and non-AIDS-defining cancers: ANRS CO3 Aquitaine cohort, 1998 to 

2006. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 

2008; Boston, Mass. Abstract 15. 

Lodwick R, Porter K, Sabin C, et al, and Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients. 

Age- and sex-specific death rates in ART-naive patients with CD4 count above 350 cells/mm3 compared with the general 

population. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 

2008; Boston, Mass. Abstract 141. 

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1- infected 

adults and adolescents (PDF). Washington, DC: US Dept of Health and Human Services; January 29, 2008. 

11. Hammer SM, Eron JJ, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the 

International AIDS Society-USA Panel. JAMA. August 6, 2008;300(5):555-570. 

12. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided 

interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296. 

13. Kitahata MM, Gange SJ, Moore RD, and The North American AIDS Cohort Collaboration On Research And Design. Initiating 

rather than deferring HAART at a CD4+ count between 351-500 cells/mm3 is associated with improved survival. In: Program and 

abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-896b. 

14. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy 

postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. July 17, 

2002;288(3):321-333.


15. Keruly JC, Moore RD. Immune status at presentation to care did not improve among antiretroviral-naive persons from 1990 

to 2006. Clin Infect Dis. November 15, 2007;45(10):1369-1374. 

16. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and 

pregnant women in health-care settings. MMWR Recomm Rep. September 22, 2006;55(RR14):1-17. 

17. 

Kuller LH, Tracy R, Belloso W, et al, for the INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and 

mortality in patients with HIV infection. PLoS Med. October 21, 2008;5(10):e203. 

18. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected 

patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. April 26, 2008;371(9622):1417-1426. 

19. Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure (VF) with abacavir/lamivudine (ABC/3TC) 

than tenofovir/emtricitabine (TDF/FTC) as part of combination therapy in treatment-naive subjects with screening HIV RNA 

≥ 100,000 c/mL. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, 

Mexico. Abstract THAB0303. 

20. Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in 

combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. In: Program and abstracts of the 15th 

Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 774. 

21. The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of 

myocardial infarction in HIV-infected patients. AIDS. September 12, 2008;22(14):F17-F24. 

22. Cutrell A, Hernandez J, Yeo J, Brothers C, Burkle W, Spreen W. Is abacavir (ABC)-containing combination antiretroviral 

therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical 

trials. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. 

Abstract WEAB0106. 

23. Pappa K, Hernandez J, Ha B, Shaefer M, Brothers C, Liao Q. Abacavir/lamivudine (ABC/3TC) shows robust virologic 

responses in ART-naive patients for baseline (BL) viral loads (VL) of ≥ 100,000 c/mL and < 100,000 c/mL by endpoint 

used in ACTG5202. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, 

Mexico. Abstract THAB0304. 

24. Hutter G, Nowak D, Mossner M, et al. Treatment of HIV-1 infection by allogeneic CCR5-D32/D32 stem cell 

transplantation: a promising approach. In: Program and abstracts of the 15th Conference on Retroviruses and 

Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 719. 

25. Hassett JM, Zaroulis CG, Greenberg ML, Siegal FP. Bone marrow transplantation in AIDS. N Engl J Med. September 15, 

1983;309(11):665. 

26. Lane HC, Masur H, Gelmann EP, Fauci AS. Therapeutic approaches to patients with AIDS (PDF). Cancer Res. September 

1, 1985;45(Suppl 9):4674s-4676s. 

27. Lennox J, DeJesus E, Lazzarin A, et al. STARTMRK, a phase III study of the safety & efficacy of raltegravir (RAL)-based vs 

efavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients. In: Program and abstracts of the 48th 

Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-896a. 

28. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, 

maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of 

antiretroviral naive subjects infected with R5 HIV-1: week 48 results of the MERIT study. In: Program and abstracts of the 

4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, 

Australia. Abstract WESS104.

References 


29. Heera J, Saag M, Ive P, et al. Virological correlates associated with treatment failure at week 48 in the phase 3 study 

of maraviroc in treatment-naive patients. In: Program and abstracts of the 15th Conference on Retroviruses and 

Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 40LB. 

30. Saag M, Heera J, Goodrich J, et al. Reanalysis of the MERIT study with the enhanced Trofile assay. In: Program and 

abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract 

H-1232a. 

31. Su Z, Reeves JD, Krambrink A, et al, and the ACTG 5211 Team. Response to vicriviroc (VCV) in HIV-infected treatment-experienced 

subjects using an enhanced Trofile HIV co-receptor tropism assay: reanalysis of ACTG 5211 results. In: Program and 

abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract 

H-895. 

32. Zolopa A, Andersen J, Komarow L, et al, and the ACTG A5164 Study Team. Immediate vs deferred ART in the setting 

of acute AIDS-related opportunistic infection: final results of a randomized strategy trial, ACTG A5164. In: Program and 

abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. 

Abstract 142. 

33. Croda J, Croda M, Neves A, Santos SDS. Impact of antiretroviral therapy in survival of HIV-infected patients admitted to 

intensive care unit. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, 

Mexico. Abstract TUPE0105. 

34. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV from persons aware and unaware that they are 

infected with the virus in the USA. AIDS. June 26, 2006;20(10):1447-1450. 

35. Bartlett JG, Branson BM, Fenton K, Hauschild BC, Miller V, Mayer KH. Opt-out testing for human immunodeficiency virus 

in the United States: progress and challenges. JAMA. August 27, 2008;300(8):945-951. 

36. Heijman T, Stolte I, Thiesbrummel H, et al. Opting out increases HIV testing in a large STI outpatient clinic. Sex Transm Infect. 

December 22, 2008. [Epub ahead of print] 

37. 

Dukers NHTM, Niekamp A-M, Vergoossen MMH, Hoebe CJPA. Effectiveness of opting-out strategy for HIV testing; 

evaluation of four years of standard HIV testing in an STI clinic. Sex Transm Infect. December 22, 2008. [Epub ahead of print] 

38. Price H, Birchall J, Newey C, et al. HIV opt-out increases HIV testing in low-risk patients. Int J STD AIDS. January 

2009;20(1):56-57. 

39. Qaseem A, Snow V, Shekelle P, Hopkins Jr R, Owens DK, for the Clinical Efficacy Assessment Subcommittee of the 

American College of Physicians. Screening for HIV infection in health care settings: a guidance statement from the American 

College of Physicians and HIV Medicine Association. Ann Intern Med. January 20, 2009;150(2). [Epub ahead of print] 

40. Hall HI, Song R, Rhodes P, et al, for the HIV Incidence Surveillance Group. Estimation of HIV incidence in the United 

States. JAMA. August 6, 2008;300(5):520-529. 

41. Valdiserri R. The HIV/AIDS epidemic in MSM in the United States. In: Program and abstracts of the XVII International AIDS 

Conference; August 3-8, 2008; Mexico City, Mexico. Abstract WEAC0303. 

42. Wilson P, Wright K, Isbell MT. Left behind: black America: a neglected priority in the global AIDS epidemic. Los Angeles, 

California: Black AIDS Institute; August 2008. 

43. Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. 

Annals of Internal Medicine. April 15, 1995;122(8):573-579.


44. Madruga JV, Cahn P, Grinsztejn B, et al, on behalf of the DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in 

treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled 

trial. Lancet. July 7, 2007;370(9581):29-38. 

45. Lazzarin A, Campbell T, Clotet B, et al, on behalf of the DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in 

treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled 

trial. Lancet. July 7, 2007;370(9581):39-48. 

46. Steigbigel RT, Cooper DA, Kumar PN, et al, for the BENCHMRK Study Teams. Raltegravir with optimized background 

therapy for resistant HIV-1 infection. N Engl J Med. July 24, 2008;359(4):339-354. 

47. Haubrich R, Eron J, Thompson M, et al. Reduction in AIDS defining events/death (ADE/D) with etravirine (ETR) compared 

to placebo (PL): pooled DUET 48 week results. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual 

Meeting; October 25-28, 2008; Washington, D.C. Abstract H-1239. 

48. Eron JE, Nguyen BY, Steigbigel RT, et al. AIDS defining conditions (ADCs) in the BENCHMRK -1 and -2 trials: 48 

week analysis. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; 

Washington, D.C. Abstract H-1249. 

49. Overton ET, Mondy K, Bush T, et al, and SUN Study Investigators. Factors associated with low bone mineral density in 

a large cohort of HIV-infected US adults: baseline results from the SUN study. In: Program and abstracts of the 14th 

Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 836. 

50. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. 

AIDS. November 14, 2006;20(17):2165-2174. 

51. Powderly W, Cohen C, Gallant J, Lu B, Enejosa J, Cheng A, and Study 903 Team. Similar incidence of osteopenia and 

osteoporosis in ART-naive patients treated with tenofovir DF or stavudine in combination with lamivudine and efavirenz 

over 144 weeks. In: Program and abstracts of the 12th Conference of Retroviruses and Opportunistic Infections; February 

22-25, 2005; Boston, Mass. Abstract 823. 

52. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus 

non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. September 2008;93(9):3499-3504. 

53. Grund B, Carr A, and The Insight SMART Study Group. Continuous antiretroviral therapy (ART) decreases bone mineral 

density: results from the SMART study. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; 

October 25-28, 2008; Washington, D.C. Abstract H-2312a. 

54. McComsey GA, Kendall MA, Tebas P, et al. Alendronate with calcium and vitamin D supplementation is safe and effective 

for the treatment of decreased bone mineral density in HIV. AIDS. November 30, 2007;21(18):2473-2482. 

55. Brown TT, McComsey GA. Osteopenia and osteoporosis in patients with HIV: a review of current concepts. Curr Infect 

Dis Rep. March 2006;8(2):162-170. 

56. Chigwedere P, Seage G, Gruskin S, Lee T-H, Essex M. Estimating the lost benefits of antiretroviral drug use in South 

Africa. J Acquir Immune Defic Syndr. December 1, 2008;49(4):410-415.

CME/CE Activity Post-Test 


RELEASE DATE: February 27, 2009 

EXPIRATION DATE: February 27, 2010 


To receive continuing education credit for this activity, you must complete all of the following pages: the post-test, 

course evaluation, as well as the credit application (pages 53, 54, 55, 56 and 57). There is no charge for this activity. 

Please be sure to answer all questions. A score of 70% or greater is required to pass this post-test. 

1. The SMART trial finds that: 

A. Interrupting or deferring HIV therapy among patients with relatively high CD4+ cell counts was associated 

with an increased risk of death from AIDS-related and non-AIDS-related causes. 

B. Levels of IL-6 and hs-CRP, as well as D-dimer, were higher at baseline among participants who died during 

the study than those who did not. 

C. Significantly greater increases in IL-6, hs-CRP and D-dimer levels were observed in the treatment 

interruption/deferral arm than the continuous HIV treatment arm. 

D. Significantly greater decreases in bone mineral density were observed with treatment continuation compared 

to treatment interruption/deferral. 

E. All the above. 

2. Related to treatment with abacavir, which of the following recent study findings are TRUE? 

A. In the D:A:D cohort study, high rates of abacavir hypersensitivity were associated with treatment disruption. 

B. Virologic failure was higher among ACTG study A5202 participants with a screening viral load of 100,000 

copies/mL who were randomized to abacavir/lamivudine compared to those randomized to 

tenofovir/emtricitabine. 

C. Analysis of the treatment continuation arm of the SMART study found that rates of cardiovascular disease 

were higher among those receiving abacavir at baseline than among those on other NRTIs. 

D. All the above. 

E. Only B and C. 

3. Which of the following statements regarding the clinical trials of raltegravir (STARTMRK) and maraviroc (MERIT) 

among treatment-naive patients are CORRECT? 

A. In STARTMRK, a large head-to-head study with efavirenz, raltegravir was found at 48 weeks to be as 

efficacious in reducing HIV RNA levels to less than 50 copies/mL. 

B. In the primary analysis of the MERIT trial, which pitted maraviroc against efavirenz, fewer patients on maraviroc 

achieved a viral load of less than 50 copies/mL at week 48. 

C. Excluding patients with non-CCR5-tropic virus from the MERIT study results in similar rates of viral 

suppression in both study arms at week 48. 

D. A, B and C. 

E. None of the above.


4. The revision in the U.S. CDC’s estimated incidence of HIV infection is a reflection of which of the following? 

A. The increase from 40,000 to 56,300 cases per year is a consequence of improvements in the reporting of HIV 

infections by states and the use of remnant blood to identify recent infections. 

B. A true 40% increase in HIV infections over the past five years. 

C. A reversal of a White House conspiracy to suppress an embarrassingly high rate of HIV infection. 

D. The original figures, supplied by a firm owned by Bernie Madoff, were found to be made up. 

E. Most of the new infections are among heterosexual females. 

5. The initiation of HIV therapy during an acute opportunistic infection was found in an ACTG trial to reduce the rate 

of progression to AIDS or death compared with deferring HIV therapy until after the treatment of the condition. True 

or false? 

A. True 

B. False 

6. Each of the following statements about opt-out testing for HIV as recommended by the U.S. CDC is true EXCEPT: 

A. Written informed consent prior to testing is not required. 

B. Intensive pre-test counseling need not be performed. 

C. The clinician need not inform the patient that the HIV test is being conducted. 

D. In studies conducted in sexually transmitted diseases clinics, this testing strategy has increased the number of 

patients being tested. 

E. State laws may have to be changed to permit opt-out HIV testing. 

7. The DUET trial of etravirine and the BENCHMRK trial of raltegravir, both in treatment-experienced patients, are 

notable for which of the following (besides using lame acronyms)? 

A. Only BENCHMRK demonstrated an improved virologic response with the study drug compared to placebo. 

B. Both trials demonstrated reductions in AIDS-defining illnesses. 

C. Etravirine had no effect on hospitalization rates or duration. 

D. A and B. 

E. A, B and C.

Post-Activity Course Evaluation 





To receive continuing education credit for this activity, you must complete all of the following pages: the post-test, 

course evaluation, as well as the credit application (pages 53, 54, 55, 56 and 57). 

General Questions: For each of the following questions, please circle the word that best describes your 

opinion. 

1. How would you rate how well the faculty presented the information within this activity? 

Excellent Very good Good Fair Poor 

2. How would you rate the quality of the content presented within this activity? 


3. How well did this activity avoid commercial bias and present content that was fair and balanced? 


4. What is the likelihood you will change the way you practice based on what you learned in this activity? 


5. Overall, how would you rate this activity? 


6. How well were you able to achieve each of the following course objectives for this activity? 

Explain the possible clinical ramifications of the most significant HIV-related studies, reports and other clinical 

developments in HIV that took place in 2008. 

Very Somewhat Not at all 

Recount the latest developments regarding the efficacy and toxicity of HIV antiretroviral agents, HAART regimens 

and treatment strategies, based on vital research published or presented in 2008. 


Describe the results of selected research developments in 2008 regarding the transmission or acquisition of HIV. 


Cite the findings of key, selected studies published or presented in 2008 regarding morbidities and mortality in HIV- 

infected persons. 


Additional Questions: Please share any other thoughts you may have about this activity. 

7. Please tell us the number of minutes you needed to complete this activity.


8. How did you hear about this CME/CE activity? 

A. Browsing through The Body PRO 

B. Browsing through The Body, The Body PRO’s sister site for patients 

C. The Body PRO E-Mail Newsletter 

D. The Body PRO Fax Newsletter 

E. Referred by a colleague 

F. Read the online version 

G. Read about it in another publication (please specify): 

H. Other (please specify): 

9. What was the most important reason you decided to take this activity? 

A. Wanted to improve my knowledge on the topic for personal reasons 

B. Wanted to improve my knowledge on the topic for clinical reasons 

C. Wanted to earn some quick, free CME or CE credit 

D. Recommended by my employer/supervisor 

E. Other (please specify): 

10. Is there anything you found particularly outstanding or noteworthy about this activity? 

11. Is there anything about this activity that fell short of your expectations? 

12. What other topics or authors would you like to see in future CME/CE activities from The Body PRO? 

13. Do you have any other comments about this activity, or about The Body PRO’s CME/CE activities in general?

Credit Application 





To receive continuing education credit for this activity, you must complete all of the following pages: the post-test, course 

evaluation, as well as the credit application (pages 53, 54, 55, 56 and 57). 

Please Note: 

• Be sure to print clearly; illegible applications will result in a delay! 

• We cannot accept applications for credit after the expiration date listed above. 

• Please allow 6 to 8 weeks to receive your certificate. 

Name: 

Profession: 

License #: 

State of License: 

Street Address: 

City: State: ZIP: 

Please circle how many HIV-infected patients your practice sees: 

Zero 1-10 11-50 51-100 More than 100 

Please circle which type of credit you are requesting: 

ACCME ANCC ACPE 

Please fill in the number of actual hours it took you to complete this activity. 

Number of Hours: (1.5 hours max for physicians; 1.5 for nurses; 1.5 for pharmacists) 

I certify that I participated in “Top 10 HIV Clinical Developments of 2008,” and that the information I have 

provided is accurate and current. 

Signature: Date: 

Would you like to receive The Body PRO’s biweekly newsletters on breaking HIV research? 

Yes No E-mail address 

To receive continuing education credit, please complete pages 53, 54, 55, 56 and 57, and fax or mail to: 

Fax: 1-603-457-6536 

Address: 

Top 10 HIV Clinical Developments of 2008 CME/CE 




Online: This activity can also be taken online at www.thebodypro.com/cme

Need More CME/CE Credits? Prefer Earning Credit Online? 

Visit CME/CE Central at The Body PRO: www.thebodypro.com/cme 

The Body PRO Features: 

CONFERENCE COVERAGE: 

Read or listen to in-depth reports from our outstanding 

faculty of the most important studies from the year’s major 

conferences. 

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Get a clinical-care focus on the latest developments in HIV 

care by browsing through The Body PRO’s engaging HIV 

JournalView. 

TREATMENT LIBRARY: 

Read daily breaking news or browse our comprehensive 

online library, featuring a wealth of information on HIV clinical 

management, new antiretrovirals and HIV/AIDS policy. 

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in clinical care. 




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The Body PRO is the sister site of www.TheBody.com, the 

Internet’s most widely visited source of HIV/AIDS information.

Top 10 HIV Clinical Developments of 2008 - CD8 T cells - The Body

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