HIV JournalView

HIV JournalView

June 2008

Table of Contents

A New Agent for HIV-Associated Abnormal Visceral Fat Accumulation

A review of:
Metabolic effects of a growth hormone-releasing factor in patients with HIV. Julian Falutz, Soraya Allas, Koenraad Blot, Diane Potvin, Donald Kotler, Michael Somero, Daniel Berger, Stephen Brown, Gary Richmond, Jeffrey Fessel, Ralph Turner, Steven Grinspoon. The New England Journal of Medicine. December 6, 2007;357(23):2359-2370.


Randomized, placebo-controlled, multi-center trial of tesamorelin in HIV-infected men and women with excessive abdominal fat.

412 patients with elevated waist circumference or waist-to-hip ratio.

Main Results
Over 26 weeks, tesamorelin produced a 15% decrease in visceral fat compared to a 5% increase seen with placebo (P < .001). The decline in fat was noticed by patients in the active treatment arm. Limb fat slightly decreased with tesamorelin, but was generally well-tolerated and improved most lipid parameters.

Tesamorelin produced meaningful declines in visceral fat without major toxicity. This is welcome news for patients with increased abdominal fat during HAART.

HIV-infected people, whose belly fat has increased substantially, desperately yearn for a magic pill to melt away their paunch. Until now, recombinant growth hormone (RHGH) was the only therapeutic option with any decent evidence of an impact on visceral fat. But, for most RHGH has been cruelly elusive due to its exorbitant price tag. Even among those with the means, the drug can produce a nasty list of adverse effects that limit lead some to stop treatment.

Hope now comes in the form of a growth hormone-releasing factor (GHRF) analog called tesamorelin. GHRF is a step up in the hypothalamus-pituitary ladder from growth hormone and prompts the endogenous release of growth hormone at levels that are more physiologic. Small preliminary studies of tesamorelin have found that it reduces visceral fat in HIV-infected individuals without much in the way of subcutaneous fat loss or major toxicities -- justifying larger randomized trials.1,2

In this study, 412 HIV-infected men and women who were receiving antiretroviral therapy and had excessive abdominal fat (for men this meant a waist circumference of at least 95 cm and a waist-to-hip ratio of 0.94, and for women this meant a waist circumference of at least 94 cm and a waist-to-hip ratio of 0.88) were enrolled at 43 sites in Canada and the United States.3

Participants were assigned 2-to-1 to a 2-mg subcutaneous injection of tesamorelin each morning or placebo for 26 weeks. After 26 weeks, patients who had initially been assigned to active drug were randomized again, this time 3-to-1, to continue to receive tesamorelin or to switch to placebo for 26 additional weeks. Patients who had been originally assigned to placebo were changed to active drug at 26 weeks.

The main outcome measure was the percentage change in visceral adipose tissue from baseline to week 26, as measured by single slice CT (computed tomography) scan at the L4 to L5 region. DEXA (dual energy X-ray absorptiometry) scans were preformed to assess regional fat depots and lean body mass. Participant perception of body shape, lipids and insulin-like growth factor-1 were secondary endpoints.

Of the 412 participants, 275 were randomized to tesamorelin and 137 to placebo. At 26 weeks, visceral adipose tissue declined 27.8 cm among those on tesamorelin compared with an increase of 5.1 cm among those who were receiving placebo (P < .001). This translated into a decrease in visceral fat of approximately 15% in the tesamorelin group versus a 5% gain in the control group.

Looking at waist circumference, patients who had been assigned to tesamorelin experienced a 2.5-cm reduction over the first 26 weeks of the study, while the placebo-assigned patients saw a 0.8-cm decline.

Not surprisingly, given the reduction in waist size, participants in the active drug arm noted the improvement in their belly size when they took the body shape surveys. Importantly, the change in visceral adipose volume with the study drug was greater among patients who had more visceral fat at baseline and was similar for both men and women.

Subcutaneous abdominal fat has been noted to decline among some patients treated with growth hormone,4 and in this trial, "pinch-an-inch" belly fat declined 0.4% in the tesamorelin group and increased 1.7% in the placebo group (P = .05). Likewise, limb fat dropped ever so slightly with tesamorelin (0.6%), but increased (3.8%) with placebo (P = .006).

Lipid-wise, tesamorelin was found to reduce triglycerides (7.5% versus an 11.6% gain with placebo), reduce total cholesterol (3.3% versus a 0.7% gain with placebo) and increase HDL [high-density lipoprotein] cholesterol (4.1% versus a loss of 1% with placebo) -- these differences in lipid parameters were all statistically significant.

Tesamorelin did not have a significant impact on glucose (fasting and 2-hour glucose tolerance) or insulin levels. No clinical or laboratory adverse event stood out to distinguish active drug from placebo; however, more patients assigned to tesamorelin discontinued study drug (22.7% versus 16.1%). Among those stopping tesamorelin, the growth hormone-associated adverse events of arthralgia and swelling, as well as injection site reactions, were common. In addition, urticaria extending beyond the injection site was seen in six tesamorelin patients, and all of them had IgG antibodies against tesamorelin.

The Bottom Line

Adapted from Julian Falutz et al. The New England Journal of Medicine. December 6, 2007;357(23):2359-2370.
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As the clinical research data continue to demonstrate the effectiveness and safety of tesamorelin for the treatment of visceral fat accumulation in HIV-infected patients, interest in this drug will increase. This will only be fueled as the findings from other studies of the drug are released.

These results, from this large clinical trial, are impressive -- tesamorelin was capable of producing a substantial reduction in visceral fat while mostly sparing subcutaneous fat. Lipid levels and glycemic parameters were not worsened and this injectable drug was reasonably well-tolerated. The only thing the drug didn't do was cure baldness. These results are welcome news for patients who look down only to see a frustratingly stubborn spare tire instead of their loafers.

Additional trials of tesamorelin are underway (this author is a site investigator for one such trial, the 26-week results of which found very similar changes in visceral fat with tesamorelin compared to placebo as observed in the trial described above). One imagines it will not be long before FDA approval for a lipodystrophy indication will be sought. When the time does come for tesamorelin to go mainstream, the HIV community -- well aware of how inaccessible recombinant growth hormone has been -- will surely be (better be) watching closely to see how the drug is priced.

The Rise and Fall (and Rise and Fall Again) of Abacavir

A review of:
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. and Risk of myocardial infarction and nucleoside analogues. James H. Stein, Judith S. Currier. The Lancet. April 26, 2008;371(9622):1391-1392.


Observational cohort study of HIV-infected patients in Europe, Australia and the U.S.

33,347 patients with HIV infection -- majority receiving HAART.

Main Results
Abacavir and didanosine were found to be associated with risk of MI, raising risk by 90% and 49%, respectively. Modeling suggested that it is use of these agents during the previous six months that is associated with MI. Risk was greatest in those with high risk of CVD due to traditional risk factors.

Abacavir and didanosine were found to be associated with risk of MI, raising risk by 90% and 49%, respectively. Modeling suggested that it is use of these agents during the previous six months that is associated with MI. Risk was greatest in those with high risk of CVD due to traditional risk factors.

The travails of the guanosine analog abacavir sulfate (ABC, Ziagen) are tortuous, if not tortured. Initially considered a potential heir of stavudine (d4T, Zerit) for the zidovudine (AZT, Retrovir)-alternative crown, this nucleoside reverse transcriptase inhibitor (NRTI) has seen its fortunes swing widely during the decade since it was first approved by the FDA as an antiretroviral.

Hardly an exciting advance in HIV therapeutics when first released, abacavir use dramatically increased with the brilliantly co-formulated Trizivir, the first triple HIV drug formulation. In this single-class formulation, abacavir was combined with zidovudine and lamivudine (3TC, Epivir) in a single pill to be taken twice a day.

In the pre-Atripla [EFV/TDF/FTC, efavirenz/tenofovir/emtricitabine] universe, Trizivir was a darling drug -- reached for by HIV care providers in clinics across the country when patients grew tired of the lifestyle contortions required by the at-the-time standard protease inhibitor (PI)-containing regimens of the day. The beauty of one pill, one prescription and one copay cannot be understated, and it even outweighed the skull and crossbones warning about hypersensitivity reactions (HSRs).

So it remained, until AIDS Clinical Trials Group (ACTG) study A5095 came along in 2004 and we learned that, while most of the patients treated with Trizivir achieved suppression of their HIV viremia, they did so in significantly fewer numbers than patients who received an efavirenz (EFV, Sustiva, Stocrin)-based regimen -- either combined with Trizivir or combined with just zidovudine and lamivudine.5

These results, and others from studies demonstrating the vulnerability of some PI-free regimens that included abacavir but no thymidine analog,6,7 dimmed abacavir's star for quite some time. A lift came with the advent of the one pill once-a-day co-formulation of abacavir and lamivudine, called Epzicom. However, the nagging abacavir hypersensitivity problem, which occurred in up to 5 to 10%,8 kept the drug from being preferred to its sleek new competitor, Truvada (TDF/FTC, tenofovir/emtricitabine).

In an attempt to neutralize the HSR issue, the maker of abacavir embarked on an ambitious series of investigations to identify patients who are genetically predisposed to the reaction. After several years, researchers discovered an association between HLA-B*5701 and HSR that at last led to the clinical use of genetic profiling to protect patients from an adverse reaction.9,10 This gave this nucleoside yet another new lease on life, and it ascended to the preferred initial antiretroviral list in the U.S. Department of Health and Human Services (DHHS) HIV treatment guidelines.11

To Construct an Antiretroviral Regimen, Select 1 Component from Column A + 1 from Column B
 Column A (NNRTI or PI Options -- in alphabetical order)  Column B (Dual-NRTI Options)
Preferred ComponentsNNRTI
efavirenz1 (AII)
or PI
atazanavir + ritonavir (AIII)
fosamprenavir + ritonavir (2x/day) (AII)
lopinavir/ritonavir2 (2x/day) (AII) (coformulated)
+Preferred Components (alphabetical order)abacavir/lamivudine3 (for patients who test negative for HLAB*5701) (coformulated) (AII); or
tenofovir/emtricitabine3 (coformulated) (AII)
Alternative to Preferred Components NNRTI
nevirapine4 (BII)
or PI
atazanavir5 (BII)
fosamprenavir (BII)
fosamprenavir + ritonavir (1x/day) (BII)
lopinavir/ritonavir (1x/day) (BII) (coformulated)
saquinavir + ritonavir (BII)
Alternative to Preferred Components
(order of preference)
zidovudine/lamivudine3 (coformulated) (BII); or
didanosine + (emtricitabine or lamivudine) (BII)

1 Efavirenz is not recommended for use in the first trimester of pregnancy or in sexually active women with childbearing potential who are not using effective contraception.

2 The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred PI component was based on twice-daily dosing [141]. A smaller study has shown similar efficacy with once-daily dosing but also showed a higher incidence of moderate to severe diarrhea with the once-daily regimen (16% vs. 5%). In addition, once-daily dosing may be insufficient for those with viral loads >100,000 copies/mL.

3 Emtricitabine may be used in place of lamivudine and vice versa.

4 Nevirapine should not be initiated the following treatment-naïve patients: women with CD4 count >250 cells/mm3 or in men with CD4 count >400 cells/mm3 because of increased risk for symptomatic hepatic events in these patients.

5 Atazanavir must be boosted with ritonavir if used in combination with efavirenz or tenofovir.

But the cheers arising from the GlaxoSmithKline (GSK) campus in North Carolina were cut short by a double whammy of clinical investigations -- the first, which was presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008), finding an association between abacavir and myocardial infarction (MI)12 and a second a few months later from a data and safety monitoring review of an on going ACTG trial (A5202) that suggested lower rates of virologic suppression among participants with high HIV RNA levels who were receiving Epzicom rather than Truvada.13 Even the most cold-hearted and hard-core Truvada fan could not help but feel a tinge of sympathy for our colleagues at GSK.

The results of the D:A:D cohort study linking abacavir and MI have been widely reported since the results were first presented as a poster at CROI 2008.12 In April, the results were published in The Lancet,14 accompanied by a thoughtful editorial by cardiologist James Stein and HIV complications guru Judith Currier15 and a letter16 describing a GSK examination of cardiovascular disease (CVD) in GSK-sponsored studies of abacavir.

The paper added little to what was contained in the well-crafted CROI poster.12 Greater detail regarding the statistical methods was included and we learned that of the 517 MIs reported during this study of 33,347 patients, the median CD4+ cell count prior to MI was 420 cells/mm3 and half of the patients had a viral load below 50 copies/mL.14 Rates of MI were 90% and 49% greater among those with recent exposure to abacavir or didanosine (ddI, Videx), respectively, relative to those without recent use of these agents. Sensitivity analyses examining the two-month period following the initiation of abacavir (when HSR is most likely) did not change the finding of an association between this agent and MI. Likewise, neither PI nor non-nucleoside reverse transcriptase inhibitor (NNRTI) use was found to interact to influence these results.

Importantly, patients who were at higher risk for cardiovascular disease not only had a higher rate of MI (no surprise), but the association between recent abacavir use and MI was strongest among these patients compared to those with a lower risk of heart disease. Although patients treated with abacavir tended to have greater overall risk of cardiovascular disease, the major findings of the study persisted after adjusting for the known factors associated with MI.

Adapted from Daniel R. Kuritzkes et al. The Journal of Infectious Diseases. March 15, 2008;197(6):867-870.
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As a counterpoint to the remarkable D:A:D study results, GSK submitted a letter highlighting their analysis of 54 studies of abacavir, including 13 randomized trials, that found that among 14,683 patients (9,639 on abacavir) there was no difference in rates of MI or other ischemic coronary events seen among those receiving or not receiving abacavir.16

The rate of MI was 2.04/1,000 patient-years in those receiving abacavir versus 2.36 /1,000 patient-years in those not treated with this agent (P = .06, with the trend favoring abacavir).

In their editorial, Drs. Stein and Currier acknowledge the serious questions regarding the safety of abacavir and didanosine that were raised by the D:A:D study, but they caution against over reacting to data that surface from observational studies.15

The low absolute risk associated with abacavir exposure among those with low or moderate risk of cardiovascular disease should be reassuring to both patients who are taking this drug and their clinicians. For those at higher risk of MI, these results need to be balanced by the potential risks of antiretroviral substitution. In all, patients' attention to modifiable cardiovascular disease risks, such as smoking, which can trump any actual effect of antiretroviral therapy, is paramount.

The Bottom Line


Retrospective cohort study.

41,213 HIV-infected patients cared for within the VA system.

Main Results
From 1995-2003, all-cause HIV-mortality fell substantially among HIV-infected patients at the VA. However, rates of hospitalization for CVD were low and remained stable during this period.

This study serves as a counterpoint to others that found a link between HAART and CVD. In this retrospective study, CVD-related mortality declined alongside of overall mortality and rates of CVD hospitalizations remained steady and low over time. These are reassuring data, but have to be considered within the context of the limitations of this retrospective analysis.

For patients taking abacavir, the latest data are a cause for confusion and concern. The D:A:D study findings are controversial, but everyone can agree that they are alarming and require additional rigorous investigation to confirm this association and identify a potential pathological mechanism.

We have limited information at this time from the A5202 data and safety monitoring board and a more comprehensive description of the results in those patients in the higher viral load stratum of the study is needed to clarify exactly how and why Epzicom underperformed relative to Truvada in that study. Undoubtedly, additional data will emerge -- from these studies and others -- that will help us better understand the risks and benefits of abacavir relative to other agents.

In my practice, I have attempted to reassure those of my patients who are taking abacavir and doing well on the drug that, from what we have been told, viral rebound was not a problem in A5202 and that I expect them to continue to enjoy virologic suppression -- even if their baseline viral load was very high.

For patients who have cardiovascular disease risk factors, I have redoubled my efforts to reduce or eliminate the most mutable of these influences by aggressively advocating smoking cessation, diet modification, vigorous exercise and lipid-lowering medications.

For a select few, there is even a doctor recommendation to drink more red wine. Few patients informed of the results of the D:A:D study opt to switch HIV medications. Many are receiving abacavir because other therapies were not an option. So they have little recourse but to continue on the medication.

In any case, the most likely alternative to Epzicom would be Truvada, yet D:A:D had an insufficient number of participants on tenofovir (TDF, Viread) to examine the risk of MI with this nucleotide analog. So, if MI risk is a concern, it is unclear what to switch to. The final chapter of the abacavir story has yet to be written. Admittedly, it is a cliffhanger. How it will end is anyone's guess.

HIV Therapy Is Not Associated With Cardiovascular Disease (This Is Not a Misprint)

A review of:
Long-term survival and serious cardiovascular events in HIV-infected patients treated with highly active antiretroviral therapy. Samuel A. Bozzette, Christopher F. Ake, Henry K. Tam, Alba Phippard, David Cohen, Daniel O. Scharfstein, Thomas A. Louis. The Journal of Acquired Immune Deficiency Syndromes. March 1, 2008;47(3):338-341.

The examination of a link between potent combination antiretroviral therapy and cardiovascular disease was first looked at in a mega-study published in 2003 in the New England Journal of Medicine.17 It made headlines for finding no apparent association between the use of combination antiretrovirals and cardiovascular events. The study was retrospective -- which was a major criticism of the research -- and centered on the U.S. Department of Veterans Affairs (VA) cohort of more than 38,000 HIV-infected patients. A landmark study, the VA paper has continued to be an important counterweight to several other studies that followed, including the D:A:D study, that have found HAART (highly active antiretroviral therapy) to be associated with a risk of MI and/or stroke.18

Adapted from Samuel A. Bozzette et al. The Journal of Acquired Immune Deficiency Syndromes. March 1, 2008;47(3):338-341.
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The authors of the original paper updated their study with an additional 2.5 years of follow-up data -- and additional patients who entered care or were newly diagnosed with HIV infection.19 The cohort now contains 41,213 individuals (98% male, 43.6% white, 32% with AIDS at diagnosis) followed for an average of four years. During the study period, there were 17,558 deaths, 1,735 inpatient stays for cardiovascular events and 19,898 occurrences of death or admission for serious cardiovascular events or stroke.

From 1995 to 2003, the all-cause mortality rate fell from 20.9 per 100 patient-years to 5.2 per 100 patient-years of observation. The rate of inpatient stay for MI or equivalent was low and stable across the study period so that the temporal trends in the rate of inpatient stay for MI, stroke or death from any cause closely mirrored that of all-cause mortality. Being older and having previous vascular disease increased the risk of cardio/cerebrovascular events and death while being of African-American race was protective (!). As was found in their original paper, no specific antiretroviral class was linked with cardiovascular events.

The Bottom Line

The authors of this update correctly highlight the impressive and often taken-for-granted survival benefits that accrue with HAART. At the same time, they, reassuringly, see no increase in the rate of serious cardiovascular events during prolonged observation of tens of thousands of patients exposed to a variety of HAART regimens. Their take-home message could be summed up as: How I learned to stop worrying about my heart and love HAART.

In this study of mostly older, HIV-infected, male veterans, the rate of admission for serious cardiovascular events was surprisingly low -- an observation shared in the D:A:D study, which found a low absolute rate of MI.18 This finding helps place the risk of cardiovascular disease during HAART in perspective as an event that, in the nearer term, is rare. Certainly, the VA study did not find that this uncommon event was made any less rare with HAART, although D:A:D has. Both studies have their limitations, and for the VA study, the absence of data on covariates (such as smoking and other cardiovascular risks) is problematic. Regardless, the shared findings of these studies vis-à-vis the overall benefits of HAART and the low risk of cardiovascular disease for most treated patients is the message that should endure from these very different, but mammoth, studies.

And, HAART Is Good for Sick Kidneys

A review of:
Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease. Robert C. Kalayjian, Nora Franceschini, Samir K. Gupta, Lynda A. Szczech, Ezekiel Mupere, Ronald J. Bosch, Marlene Smurzynski, Jeffrey M. Albert. AIDS. February 19, 2008;22(4):481-487.


Ad hoc analysis of renal function using samples and data collected during ACTG treatment trials.

1,776 HIV-infected participants in HIV treatment trials conducted by the ACTG from 1997-2004.

Main Results
Overall, GFR fell slightly during HAART, but among the subset with significant renal dysfunction at baseline, HAART was associated with improvements in GFR. Declines in HIV RNA levels with HAART were correlated with GFR improvement only among those with more advanced HIV disease.

While there is considerable concern regarding the nephrotoxicity of HIV therapies, these results suggest that a) HIV itself can produce renal insufficiency and b) HAART can actually improve kidney function for those who have renal disease.

There's a long list of organs to lose sleep over during HIV therapy, this includes the heart, liver, pancreas and brain. Recently, data implicating tenofovir in decreases in glomerular filtration have added the kidneys to this list.20

Certainly, kidney disease has long been a malicious accompaniment to HIV disease -- whether in the form of injection-drug-associated nephropathy, hypertensive and diabetic renal disease, or drug-induced nephrotoxicity -- and renal failure is not uncommon in this population. However, there are also data to suggest that HIV itself can cause HIV-associated nephropathy, either as the virus invades the glomeruli and/or due to immune complexes that are elicited during viremia.21

To examine the effect of antiretroviral-mediated suppression of HIV viremia on the glomerular filtration rate (GFR), investigators from the ACTG conducted an analysis of data collected from 1,776 participants enrolled in a super-study of ACTG treatment trials between 1997 and 2004.22 The GFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation. At enrollment, 77% of the cohort were treatment naive, 30% were black, 9.5% had hepatitis C (HCV) coinfection, 13.6% had hypertension and 4.2% had diabetes. The median GFR was 100.9 mL/min per 1.73 m2 and 82% had normal renal function at baseline.

During study follow-up, the GFR declined slightly by 0.3 mL/min per 1.73 m2 annually, but the slope of the change in renal function differed according to baseline renal status. Among the trial participants with stage 2 or worse chronic kidney disease at entry, the GFR improved significantly by 2.8 mL/min per 1.73 m2 each year and 28% of these patients achieved normal levels (greater than 90 mL/min per 1.73 m2).

Among patients who started with normal renal function, the GFR remained above the threshold for normal in about 81%. Of the 31 participants with stage 3 renal disease at baseline, 24 (77%) experienced improvements to greater than 60 mL/min per 1.73 m2, including five who achieved a GFR of greater than 90 mL/min per 1.73 m2.

Improvements in the GFR were correlated with viral suppression in patients with chronic kidney disease and CD4+ cell counts less than 200 cells/mm3. In this more advanced subset, suppression of HIV viremia by greater than 1 log10 copies/mL or to less than 400 copies/mL was associated with a mean increase in GFR of 9.2 mL/min per 1.73 m2 over a median of 160 weeks of follow-up (P = .02). These improvements were influenced by neither race nor gender.

Interestingly, improvements in GFR were seen among patients with a CD4+ cell count greater than 200 cells/mm3, although this effect was independent of viral suppression, suggesting a mechanism by which HAART improves renal function independent of changes in viremia.

The Bottom Line

The finding that the suppression of HIV burden improves renal function in those with AIDS and an abnormal GFR adds to a growing body of evidence pointing to a role of HIV itself in organ damage. Withdrawal of HIV therapy worsened cardiac, hepatic and renal outcomes in the SMART Study, implicating HIV as a proinflammatory mediator of disease of these organs, and here we see reversal of renal insufficiency with HAART.23 The finding that GFR improvement was linked to viral suppression in those with lower CD4+ cell counts supports the investigators' hypothesis that HIV itself was at least in part responsible for the renal disease in this group. That HAART also improved the GFR in those with higher CD4+ cell counts independent of viral response is curious and remains unexplained.

Overall, these are encouraging observations that suggest HIV-associated nephropathy, like HIV encephalopathy and hepatitis B (HBV) coinfection, is a condition that should prompt serious consideration of the initiation of antiretroviral therapy, regardless of CD4+ cell count -- as now advocated in the DHHS guidelines of initial treatment of HIV infection.11

Genotypic Resistance Algorithms Are Pretty Much Alike

A review of:
Comparison of algorithms that interpret genotypic HIV-1 drug resistance to determine the prevalence of transmitted drug resistance. Lin Liu, Susanne May, Douglas D. Richman, Frederick M. Hecht, Martin Markowitz, Eric S. Daar, Jean-Pierre Routy, Joseph B. Margolick, Ann C. Collier, Christopher H. Woelk, Susan J. Little, Davey M. Smith. April 23, 2008;22(7):835-839.


Analysis of the correlation among HIV resistance algorithms using data collected from patients acutely infected with HIV.

1,311 patients with acute HIV infection.

Main Results
Major resistance algorithms tended to agree regarding the interpretation of genotype data, especially among the PI and NNRTI classes. For NRTIs, the algorithms produced greater variability in their results.

The major resistance algorithms reassuringly yielded similar results, but were less harmonious when it came to NRTI resistance. For NRTIs, actual examination of the detected mutations rather than reliance of an algorithm may be prudent.

There was a time when, if you knew that D30N, M184V and K103N were mutations conferring resistance to nelfinavir (NFV, Viracept), lamivudine and the first generation of NNRTIs, respectively, you would be considered a genotype expert. Since then, the identification of a slew of additional resistance mutations, as well as the introduction of new antiretrovirals, including several in novel classes, has made resistance test interpretation more complicated.

To help our over-taxed brains, several major algorithms have been devised to infer HIV susceptibility to antiretrovirals based on genotypic resistance profiles. Most are easily accessible via the Internet and include the International AIDS Society-USA (IAS-USA), the Stanford, the Agence Nationale de Recherches sur le SIDA (ANRS) and the Rega algorithms, plus the calibrated population resistance algorithm developed for the surveillance of transmitted drug-resistant HIV. How these various methods compare across antiretroviral classes and their level of agreement were examined using data derived from 1,311 acutely HIV-infected individuals.24

Overall, across the different algorithms, the estimated prevalence of transmitted drug resistance was nearly identical when it comes to the NNRTIs.

There was slightly more variability for drugs in the PI class, but it was among the NRTIs that the methods yielded different reports regarding the prevalence of drug resistance. The commonly used Stanford database was found to be most conservative when the computed resistance score was considered to be at least 60. Using a less rigorous score of 30 put this algorithm in the middle of the pack. The Rega algorithm called resistance more often than the others -- especially among drugs in the NRTI class -- when intermediate and complete resistance were both counted. Despite this variation for NRTIs, by and large, the overall agreement of the algorithms was considered fairly high.

The Bottom Line

Adapted from Lin Liu et al. AIDS. April 23, 2008;22(7):835-839.
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Generally, the HIV resistance interpretation algorithms studied provided similar results, although there were important differences. For NRTIs, there was wider variation in the estimated prevalence of resistance compared to the other drug classes, with a 9% difference between the most conservative, the Stanford algorithm (using the more discriminating resistance score of 60), and the least conservative, the Rega algorithm (considering intermediate resistance as evidence of drug resistance). For the PI and NNRTI classes, the algorithms produced similar results.

Although tested among a cohort of acutely/recently-infected individuals, this study provides a nice comparison of these methods -- more commonly used for clinical management of HIV infection. It is reassuring to the clinicians who rely on these algorithms to know that they are more alike than different.

Baseline NNRTI Resistance and Treatment Response

A review of:
Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. Daniel R. Kuritzkes, Christina M. Lalama, Heather J. Ribaudo, Michelle Marcial, William A. Meyer III, Cecilia Shikuma, Victoria A. Johnson, Susan A. Fiscus, Richard T. D'Aquila, Bruce R. Schackman, Edward P. Acosta, Roy M. Gulick. The Journal of Infectious Diseases. March 15, 2008;197(6):867-870.

It is a tenet of HIV management that the ability of an antiretroviral to suppress the replication of virus highly resistant to that drug is slim to none. That this should hold true for acquired drug-resistant HIV would seem to fall into a category best labeled "duh."

However, when it comes to the impact of drug resistance on therapeutic outcomes, there are reasons to check one's assumptions. For one thing, there are conflicting studies, some of which demonstrate a clear adverse consequence of baseline resistance,25 while others do not find any such impact of pre-existing resistance on treatment outcome.26 In addition, it has been observed that most drug-resistant HIV strains become increasingly difficult to detect over time in the absence of selective pressure exerted by antiretroviral therapy -- leading to speculation that some of these viral strains may actually fade and, ultimately, vanish.

In ACTG study A5095, a treatment-naive trial of efavirenz plus zidovudine and lamivudine plus or minus abacavir versus zidovudine, lamivudine and abacavir [not Trizivir], 193 of the 765 participants who were receiving efavirenz experienced virologic failure (a confirmed viral load greater than 200 copies/mL at week 16 or beyond).5

>Real-time genotypic resistance testing was not performed during this study. To determine the effect of baseline NNRTI resistance on the risk of virologic failure, ACTG investigators conducted a case-cohort study using a random sample of efavirenz-assigned participants -- 26% of whom had experienced virologic failure (cases) and the remainder who had not (controls) -- plus the additional participants with virologic failure. In total, there were 193 individuals with virologic failure and 163 without virologic failure (N = 356). Of these, 342 had genotypic data and sufficient on-study follow-up.27

Overall, 5% of the random cohort had NNRTI resistance that was detected by genotype performed on baseline specimens. Among the 342 participants, 16 (8%) with virologic failure and three (2%) of those without failure, had detected NNRTI resistance. The K103N mutation was the most common NNRTI-resistance mutation found and several participants with virologic failure had more than one NNRTI-resistance mutation detected. None of the controls had multiple NNRTI mutations.

The time to virologic failure was significantly shorter for patients with baseline NNRTI mutations compared to those without such resistance. Likewise, the risk of failure was increased by pre-existing NNRTI resistance (hazard ratio, 2.27 [95% CI, 1.15-4.49], P < .018). This effect persisted after adjusting for race/ethnicity and self-reported adherence. Interestingly, three individuals with pre-entry NNRTI resistance did not experience virologic failure during the study and all were on the four-drug arm of abacavir, zidovudine, lamivudine and efavirenz.

The Bottom Line


Case-cohort study of impact of baseline drug resistance on virologic success of efavirenz-based therapy during ACTG study A5095.

342 participants in A5095 -- a prospective treatment trial of initial HIV therapies.

Main Results
5% of a random sample of A5095 participants had baseline NNRTI resistance detected by genotype, with K103N most common NNRTI mutation. Risk of virologic failure was greater if NNRTI resistance present (HR = 2.27) and time to virologic failure among these patients was significantly shorter than for those without NNRTI resistance detected.

Baseline NNRTI resistance matters. Those with detectable resistance to agents of this class (either through standard or ultrasensitive genotypic resistance testing) fare less well than those resistance-free. Testing for baseline resistance is a must and those with NNRTI resistance should avoid efavirenz and nevirapine.

Baseline NNRTI resistance detected with standard bulk sequencing genotype resistance testing was clearly associated with virologic failure in this study. Interestingly, in a follow-up analysis of this same cohort, the investigators looked at whether harboring minority variants -- mutant virus that was present at very low levels and detectable by sensitive allele-specific PCR (polymerase chain reaction) rather than the standard bulk sequencing technique -- was associated with the risk of subsequent virologic failure. They found that among patients without NNRTI resistance detected by bulk sequencing, but who did have pre-existing minority Y181C mutants, the risk of virologic failure increased more than three-fold compared to those without the variant. Modeling suggested a similar impact of pre-existent K103N mutation. Importantly, Y181C minority variants were also seen in a number of patients without virologic failure, albeit at lower rates, suggesting that the presence of drug-resistant minority variants does not guarantee failure.

The alarming results of these analyses provide substantial backing for recommendations from DHHS to conduct baseline resistance testing -- especially given the relatively high prevalence of transmitted drug resistance.11 That there are patients harboring minority variants that exist below the radar of standard resistance testing but may threaten treatment outcomes is worrisome. However, additional investigations aiming to determine the significance of these low-level mutants are underway. Meanwhile, detection of NNRTI resistance with standard baseline resistance testing should preclude the use of efavirenz or nevirapine (NVP, Viramune) in a patient's treatment regimen.

Super-Sized HBV Vaccine for Bigger Response in HIV

A review of:
A prospective open study of the efficacy of high-dose recombinant hepatitis B rechallenge vaccination in HIV-infected patients. Theodora E. M. S. de Vries-Sluijs, Bettina E. Hansen, Gerard J. J. van Doornum, Tirza Springeling, Nicole M. Evertsz, Robert A. de Man, Marchina E. van der Ende. The Journal of Infectious Diseases. January 15, 2008;197(2):292-294.


Prospective cohort study of revaccination for HBV with double dose of vaccine for those HIV-infected patients failing to mount adequate initial response.

144 HIV-infected patients who failed to develop HBsAb after standard HBV vaccine series.

Main Results
About 50% of patients had no HBsAb detected after initial series. Revaccination with double dose given three times over three months led to adequate response in 50%. Therefore, overall, initial series plus revaccination with double dose led to response in 75% of patients. Response to revaccination not associated with CD4+ cell count. Women had better responses, whereas older patients had lower response rates.

Revaccination with double-dose HBV vaccine was effective for many patients and is an option when initial response to standard vaccine is suboptimal. Larger study needed to determine if initial vaccination with double-dose vaccine will improve initial response.

Vaccines are great -- if they work. When they don't, it is the fault of either the vaccine (e.g., cholera vaccination) or the host who for some reason does not mount the intended response (e.g., transplant recipients). There are numerous reasons why patients with HIV infection can be expected to have less robust responses to a vaccine than do others. For starters, HIV-infected patients usually have suffered years of immunologic chaos marked by depleted lymphocyte counts and imbalances in immune cell populations. In addition, patients with advanced HIV disease can suffer from malnutrition -- a known risk for suboptimal immune response. Smoking, HCV coinfection and diabetes, as well as other co-morbidities, also present a challenge to vaccine efficacy in this population.

HIV and HBV share modes of transmission and coinfection is not rare.28 The HBV vaccine is an important advance in the effort to eradicate this virus from our planet; however, it is well-documented that HIV-infected patients not only remain at risk for HBV infection, but they also have a poor response to the three-shot HBV vaccine series.29

The failure to adequately protect against HBV infection in HIV-infected patients can be devastating -- risking the sequelae of chronic HBV as well as tolerability to HAART.

In some populations, notably in patients with renal failure, higher doses of HBV vaccine have been found to enhance the response to the vaccine.30 Whether the same would be the case in patients who also have HIV infection was the focus of this study from Rotterdam.31

Patients attending an infectious diseases clinic who were both HBsAg and anti-HBc negative were routinely vaccinated with the standard three-shot HBV series (HBVAXPRO 10 mcg/mL). Those who were non-responders (defined as having an anti-HBs titer of 0 IU/L) were then offered revaccination with a double dose of the vaccine at 0, 1 and 2 months. A total of 144 patients were revaccinated. Most (75%) were male, the mean BMI (body mass index) was 25.3 and the mean age was 43.4 years. Two thirds of the cohort were receiving HAART and the great majority of them had an HIV RNA level that was less than 50 copies/mL. The median nadir CD4+ cell count was 205 cells/mm3 and was 360 cells/mm3 at the time of initial HBV vaccination.

Revaccination with double-dose HBV vaccine in those who failed to respond to routine HBV vaccination led to anti-HBs titers greater than 10 IU/L in 50.7%; the median anti-HBs titer was 108 IU/L. In a multivariable analysis, women had a better response to revaccination than men. Response also tended to decrease with age, but this effect was muted among patients with undetectable HIV RNA levels.

The Bottom Line

The results suggest that high rates of HBV vaccination response can be evoked. Initial vaccination with standard HBV vaccine yielded a serological response in about 50% of patients. Of those who did not achieve this response, repeated vaccination with the high-dose HBV vaccine seroconverted an additional 50%, leading to an overall response rate of 75% in this clinic.

Previous studies that were cited by the authors in their discussion, have found initial vaccination with the higher dose HBV vaccine to be either no more effective than the standard vaccine or more potent only among patients with better CD4+ and HIV RNA parameters.32,33

Curiously, in this study and others, CD4+ cell count had no discernable independent effect on response to the vaccine -- although, in this Dutch cohort, this may be a function of the low number of individuals with a CD4+ cell count below 200 cells/mm3 (N = 26). Clearly, more work among larger groups of patients needs to be done to better understand how to best enhance HBV protection for HIV-infected patients.

Regardless, the vaccine at a high dose was well-tolerated. For clinicians frustrated with low rates of return on their HBV vaccine investments, a double-boost of HBV vaccine at monthly intervals for three months may be worth a try.


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