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Top HIV/AIDS-Related Clinical Developments of 2010

By David Alain Wohl, M.D.

December 8, 2010

Table of Contents

As an action-packed year for the HIV/AIDS community draws to a close, TheBody.com takes stock of 2010 in a new series of articles, "HIV/AIDS Year in Review: Looking Back on 2010 (and Ahead to 2011)." Read the entire series here.


Introduction

David Wohl, M.D.

David Wohl, M.D.

The first year of a new decade, 2010 could have been the year of hope. Political spin masters dangled it before our eyes -- luring us, a divided nation, to come to their side -- only to cause more division. As the economic crisis continues to put the hammer to life as we know it, hope is all that many of us feel we have left as we try to make do with less.

In HIV-land, we also hope -- for better therapies for those living with HIV and for the beginning of the end of an epidemic that is just getting old. This past year, we saw some bright glimmers of success where before there was stagnation. A series of remarkably positive results in HIV prevention promises to move us into a new era of interventions designed to stop people from giving each other HIV. In HIV therapeutics, the pipeline of new antiretrovirals has spurted again and additional coformulation of these and older medications will mean even more convenient choices for patients.

Such developments made for a better year in HIV than many could have expected given the grim headlines. They signal, as we move through the tweens to the teens of this decade, that the prevention of new infections and the care for those who acquire HIV will continue to advance; that HIV research will continue to be a marvel of medicine; that there is good reason to hope.


CAPRISA: A Home Run (or at Least a Base Hit) for a Microbicide

A review of:
Karim QA, Karim SSA, Frohlich JA, et al, on behalf of the CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
Science [serial online]. September 3, 2010;329(5996):1168-1174. Published online July 19, 2010. Available at: www.sciencemag.org/content/329/5996/1168.full.html. Accessed August 1, 2010.

Controlling the spread of HIV has been a vexing and complex public health challenge. The physical mechanics are really not the problem: Keeping one person's virus-laden fluids away from the vulnerable cells of another is something most with a well-developed frontal cortex can figure out how to do, technically speaking. But latex barriers -- despite their colorful names, choices of textures, and fruit-inspired flavors -- have just not cut it, and efforts that rely heavily on getting men to put on condoms can be summed up with a word: failed.

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There have been a number of different creative approaches to the whole keep-your-virus-off-my-cells approach, including protective and therapeutic vaccines, male circumcision, pre- and post-exposure prophylactic treatment and microbicides. However, with the important exception of circumcision -- which has demonstrated modest success in preventing HIV transmission, but has its own drawbacks and limitations -- these strategies have had poor efficacy, leading to much head hanging and dour faces at HIV prevention conferences.

One can therefore understand the ebullient and triumphant response that greeted the first public report of the results of a Centre for the AIDS Programme of Research in South Africa (CAPRISA) trial this year at the XVIII International AIDS Conference held in Vienna.

CAPRISA 004 was a South Africa-led trial of a 1% tenofovir (Viread) vaginal gel that enrolled HIV-uninfected women 18 to 40 years of age at two clinical sites in that country, one urban and the other rural. The trial was a double-blind study. Participants were provided with pre-filled vaginal applicators (those that contained the study gel were indistinguishable from those that contained a placebo gel) and instructed to insert the assigned gel within 12 hours before sex and a second dose of gel as soon as possible within 12 hours after sex (the so-called "BAT24" approach, short for "before and after sex within 24 hours"). All participants received HIV counseling services, condoms and sexually transmitted disease screening and treatment at entry and each subsequent study visit. The enrolled women also received assistance in learning to use the gel to increase comfort and adherence.

During a maximum of 30 months of follow-up (mean was 18 months), 38 of the 445 women assigned to the active gel versus 60 of the 444 assigned placebo became infected with HIV. The HIV incidence rate in the tenofovir gel arm was 5.6 per 100 women-years (confidence interval [CI], 4.0 and 7.7) compared with 9.1 per 100 women-years (CI, 6.9 and 11.7) in the placebo gel arm (IRR = 0.61; CI, 0.40 and 0.94; P = .017). Therefore, at the primary endpoint of 30 months follow-up, the incidence rate for women receiving tenofovir gel was 39% lower than for the placebo-assigned women.

Adherence to the gels was assessed carefully; the investigators even requested that women return used applicators, which were then inspected for signs of use. Remarkably, over 95% of applicators were returned. Women in both study groups reported a mean of approximately 5 sex acts per month. Self-reported condom use was high at around 80%. When looking at adherence and efficacy, it was observed that among those with greater adherence, the effect size increased: Even fewer women in the tenofovir arm acquired HIV relative to the control arm. Elegant studies led by Dr. Angela Kashuba looking at levels of tenofovir in the cervical-vaginal fluid corroborated this finding. Interestingly, the effectiveness of the tenofovir gel seemed to wane over time, with a greater effect observed early in the study. However, this may reflect a decrease in adherence to the gel over time, rather than a flaw with the gel itself.

Overall, the gel was found to be safe, although there were some complaints of the compound being a bit on the messy side. There was more diarrhea reported among those on the active gel, but otherwise tolerability was no different between the study arms. For those who did seroconvert while receiving active tenofovir gel, there was no impact seen on plasma viral load or demonstration of tenofovir resistance.

A fascinating aspect of the trial was the observation that the rate of herpes simplex virus (HSV) type 2 seroconversion during the study was less among those assigned to the tenofovir gel. A lesser-known fact is that tenofovir has activity against HSV, but only at high concentrations of the drug. It is possible that the gel achieved high enough levels in the genital tract to protect some women against HSV acquisition.

The Bottom Line

The cheers that greeted the CAPRISA trial findings were not for the modest 40% reduction in infection with tenofovir gel -- a result that would send a vaccine back to the drawing board. It was a response by a community of researchers and advocates hungry for any success of a microbicide. Prior studies of earlier compounds found not only a lack of effect but, in the case of nonoxynol-9, what actually appeared to be an increased susceptibility to HIV.

The triumph of CAPRISA 004 is a starting point. There are aspects to tweak, including the timing of applications and formulation. In addition, the trial was rigorous in describing the association between adherence and efficacy of the gel and the need to develop interventions to support women using this compound. Lastly, it is unclear whether a combination of antiretrovirals (for instance, a gel containing tenofovir plus emtricitabine [FTC, Emtriva]) would offer better protection.

There are additional studies underway and planned. Meanwhile, the prospects of a woman-controlled HIV prevention method seem much closer now than just a few months ago. Score!


iPrEx: A Tenofovir/Emtricitabine Pill a Day Keeps the HIV (Doctor) Away

A review of:
Grant RM, Lama JR, Anderson PL, et al, for the iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.
N Engl J Med [serial online]. November 23, 2010. Published online ahead of print. Available at: www.nejm.org/doi/full/10.1056/NEJMoa1011205.

If coating an orifice with tenofovir can help prevent the transmission of HIV, how about tackling the problem from the other side -- that is, take the medication orally and let it concentrate in the linings of the surfaces exposed to HIV during sex? That was the premise of the important and exciting iPrEx trial. In this study, 2,499 HIV-uninfected men and transgender women (born male) who have sex with men living in one of six countries (Peru, Ecuador, Brazil, South Africa, Thailand and the U.S.) were randomized to receive either tenofovir/emtricitabine (Truvada) once daily or a placebo. The participants were at very high risk for HIV: The median number of sex partners in the past 12 weeks prior to entry was 18 and 60% had unprotected anal sex during that time period. Tellingly, 13% had a reactive test for syphilis at baseline.

During the course of the trial (median follow-up 1.2 years), 100 participants became HIV infected: 64 in the placebo arm and 36 of those receiving the active drug. That's a 44% reduction in the incidence of HIV (95% CI, 15 to 63; P = .005) among those receiving tenofovir/emtricitabine. Importantly, in the tenofovir/emtricitabine group, the study drug was detected in the blood of 51% of those who remained HIV uninfected, but in only 9% of those who became infected. For those in the active treatment arm who had detectable levels of tenofovir/emtricitabine, the protective effect of tenofovir/emtricitabine exceeded a 90% reduction in risk.

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There were no differences between the two study arms in reported sexual practices during the study. Use of the active drug (compared to placebo) was associated with greater risk of nausea and weight loss. Further, some mild changes in renal function were seen in the tenofovir/emtricitabine arm, although this was reversible with cessation of the drug.

Among those who acquired HIV while on the active study drug, none had resistance detected to either tenofovir or emtricitabine. Ten cases of acute HIV infection at study entry were detected, and three of these had emtricitabine-resistant virus detected subsequently (2 of 2 in the active arm and 1 of 8 in the placebo arm). There was no tenofovir resistance detected among the acute infection cases.

The Bottom Line

This is a big deal. The iPrEx trial has made clear that pre-exposure prophylaxis (PrEP) is not just plausible, it actually works. The impressive reduction in new infections demonstrates that humans, like other primates, have a harder time getting infected with HIV when they have tenofovir on board.

However, the study also showcases the limitations of PrEP. Despite self-reported levels of adherence to the study medication of about 90%, it was clear from drug levels that this was an exaggeration bordering on the delusional. Those who apparently took the active therapy had a much greater benefit, but in real life many will not be adherent.

Further, tenofovir/emtricitabine did produce some side effects, which is not too surprising. It's likely that this will become an issue as use of the drug broadens. However, many women take oral contraceptives to prevent pregnancy despite the risk of potentially serious adverse events. Fortunately, the effects described in this trial were easily reversed upon stopping the drug. Therefore, many may opt to use PrEP even if there is a chance for a side effect. The potential for problems with longer-term administration, such as decreased bone mineralization, is a concern and will require dedicated study.

Other logistical issues will need to be sorted out, including who should receive the medication, who will prescribe it and who will pay for it. The population studied in iPrEx was quite high risk. Is PrEP worthwhile for those with fewer risky behaviors? What about the risk of drug resistance that may come with wider use of tenofovir/emtricitabine? Can PrEP be given intermittently, such as before an anticipated exposure to HIV, rather than daily?

As the dust settles, these are important questions that the HIV prevention and treatment communities will have to tackle. For now, as with CAPRISA, we can look to iPrEx as a major step forward and beyond the condom.


Rilpivirine: The New NNRTI on the Block

A review of:
Cohen C, Molina J-M, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind randomized, phase III trials comparing TMC278 versus efavirenz in treatment-naive, HIV-1-infected patients. In: Program and abstracts of the XVIII International AIDS Conference; July 18-23, 2010; Vienna, Austria. Abstract THLBB206.

and

Rimsky L, Eron J, Clotet B, et al. Characterization of the resistance profile of TMC278: 48-week analysis of the phase 3 studies ECHO and THRIVE. In: Program and abstracts of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2010; Boston, Mass. Abstract H-1810. Available at: www.abstractsonline.com.

New and improved! It's the exclamatory catchphrase used by the makers of everything from cereal to colas. For HIV medications, "even better" can come from playing with the chemical structure of a drug (e.g., fosamprenavir [Lexiva, Telzir]) or through new formulations that reduce pill count, size or palatability (e.g., nelfinavir [Viracept], zidovudine [AZT, Retrovir] and lopinavir/ritonavir [Kaletra]). Many of our most popular drugs have changed little other than to be included in fixed-dose combinations. Efavirenz (Sustiva, Stocrin), a flagship NNRTI (non-nucleoside reverse transcriptase inhibitor), received a great boost by being incorporated with tenofovir and emtricitabine in a formulation known as Atripla. However, it has well-understood limitations, including central nervous system (CNS) effects, the risk of serious rash and worrisome teratogenicity (risk of birth defects). More recently, efavirenz has been associated with dyslipidemia, peripheral fat loss and reduced vitamin D levels. It is a testimony to its attributes that despite these annoying problems the drug is so commonly prescribed. But there is room for improvement.

Rilpivirine (formerly TMC278) is a single-pill NNRTI with a long half life permitting once-daily dosing and which causes no apparent CNS side effects. Therefore, at face value this drug looked like a good candidate to ascend the NNRTI throne. All that remained was a couple of head-to-head trials against efavirenz: the ECHO and THRIVE studies. In the former, the NNRTIs were paired with tenofovir/emtricitabine; in the latter, clinicians were able to select from the three marketed dual-NRTI (nucleoside/nucleotide reverse transcriptase inhibitor) fixed-dose combinations. Almost 700 treatment-naive patients were enrolled in each trial.

It is notable that the dose of rilpivirine used in these studies was 25 mg daily -- the lowest among three doses that included 75 mg and 150 mg in early studies of the drug. While 75 mg was the originally selected dose for development, prolongation of the QT interval (a measurement of the pacing of the electrical activity of the heart seen on an electrocardiogram [ECG] tracing) at that dose required proceeding with the next-lowest dose studied, 25 mg.

The 48-week results of the trials were generally similar. In pooled analyses, the proportion of participants with a confirmed viral load less than 50 copies/mL (using time to loss of virologic response, which is an intent-to-treat analysis method) was 84.3% for rilpivirine and 82.3% for efavirenz. When looking at those with a baseline viral load below 100,000 copies/mL, rilpivirine tended to have a better response rate compared to efavirenz (90% vs. 84%; difference = 6.6 [95% CI: 1.6, 11.5]). However, at the higher viral load stratum (above 100,000 copies/mL), efavirenz tended to do better (81% vs. 77%; difference = -3.6 [95% CI: -9.8, 2.5]).

Importantly, the TLOVR analysis favored by the U.S. Food and Drug Administration (FDA) includes loss of viral response for reasons of virologic failure as well as drug intolerance. When comparing just the virologic failure rate between the two NNRTIs, 9.0% of those assigned to rilpivirine failed versus 4.8% of those randomized to efavirenz. Conversely, the rate of treatment failure due to adverse events was higher with efavirenz compared to rilpivirine (6.7 vs. 2.0). As expected, CNS toxicity was more common with efavirenz than with rilpivirine, as was rash (14% vs. 3%).

Among those with failure, many had no resistance mutations detected. For those with resistance, the K103N mutation emerged in those treated with efavirenz, whereas the E138K mutation was observed in the rilpivirine failures.

The Bottom Line

The findings from these two trials serve as a coming-out party for this newest member of the NNRTI family. There have been high hopes for rilpivirine to be a kinder-and-gentler efavirenz -- one that can actually be taken during daylight hours. However, this debut has come with mixed reviews. On the one hand, the results show what the studies set out to show: that rilpivirine is not worse than efavirenz. On the other hand, rilpivirine appeared to be less potent, albeit better tolerated. One cannot help but wonder whether this less-than-optimal performance is a consequence of the need to study rilpivirine at a lower dose than originally intended.

What we have with rilpivirine in the ECHO and THRIVE trials is a tradeoff between efficacy and tolerability, particularly among those with higher plasma HIV RNA levels. If and when the drug comes to market, it will be important to see whether clinicians will feel comfortable prescribing rilpivirine to those with higher HIV RNA levels (a viral load greater than 100,000 copies/mL or so). The convenience and tolerability advantages of this NNRTI, especially if it is coformulated with tenofovir and emtricitabine as planned, may trump potency concerns for some.

There are some other warts. Rilpivirine cannot be taken with proton-pump inhibitors and needs to be taken with food. Additionally, there is the sequencing issue: Failure of efavirenz can be expected to be salvaged with etravirine (TMC125, Intelence), while some patients failing rilpivirine were found to be resistant to this second-generation NNRTI.

These trials will yield additional data as the study volunteers are followed to 96 weeks. Such results may further help us understand where this new NNRTI will fit in the ever-growing list of treatment options for those initiating HIV therapy.


Attention: Quad Is in the Building

A review of:
Cohen C, Shamblaw D, Ruane P, et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, Calif. Abstract 58LB. Available at: http://retroconference.org/2010/Abstracts/39864.htm.

Just when you thought it was impossible to combine more than three HIV medications into one tablet capable of slipping past the average person's gag reflex -- at least without a major infraction of some of the most beloved laws of physics -- along comes the Quad pill. This is the nickname for a four-drug combination of tenofovir, emtricitabine, elvitegravir (formerly GS 9137, as well as JTK-303) and cobicistat (formerly GS 9350). Elvitegravir is an integrase inhibitor in development that requires pharmacological boosting with either ritonavir (Norvir) or cobicistat, an investigational booster drug.

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We learned about the existence of the Quad pill in 2009, but this year the first comparative trial of the formulation was presented. The phase 2 study was double-blind, enrolling 71 treatment-naive patients who were randomized 2:1 to receive either the Quad pill or coformulated efavirenz/tenofovir/emtricitabine.

At 48 weeks, the rate of suppression of HIV RNA to less than 50 copies/mL was 90% with Quad versus 83% for the triple-drug arm (95% CI: -8.8% to 25.6%). The mean change in CD4+ cell count was greater with Quad (240 cells/mm3) than with efavirenz/tenofovir/emtricitabine (162 cells/mm3).

The Quad pill was well tolerated. As expected, CNS adverse effects were concentrated in the efavirenz arm. The change from baseline over 48 weeks for all lipid parameters that were measured (total, low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol) increased more with the efavirenz-based regimen than the Quad, except for triglycerides, which rose to a greater extent with the Quad -- likely driven by the cobicistat.

Importantly, the change in estimated glomerular filtration rate (GFR) -- the rate at which the kidney dumps what it should into the urine -- was greater with the Quad, dropping 14% compared to 4% with the efavirenz-based triple-therapy regimen. This was explained by the researchers as an artifact and not really an impact on kidney function, since cobicistat reportedly decreases creatinine secretion into the urine. (Creatinine is a marker measured in the blood to assess kidney function.)

The Bottom Line

We are entering an era in which there will be more than one single-pill, once-daily therapy for HIV infection. All of us well appreciate the psychological significance of efavirenz/tenofovir/emtricitabine, the first single-tablet daily HIV regimen for people with HIV. Having more of them will further secure the perception that HIV therapy need not mean handfuls of pills, a dedicated medicine cabinet and an alarm clock.

The development of a non-ritonavir booster, cobicistat, has also been long awaited. The problem is that cobicistat may be a bit too much like ritonavir to be truly remarkable. In this study, triglycerides (a bane of ritonavir's existence) increased with the Quad. The funky effect of the drug on GFR readings may also be an annoyance.

However, by including two new agents and in its mind-blowing medicinal chemistry, the Quad pill enforces the idea that innovation in the field of HIV therapeutics is not moribund. People are trying to make therapies that not only work, but that patients can more easily take. Additional drugs mean additional options.

As I described above, it will remain difficult to predict which of the bite-sized items on the antiretroviral menu end up being chosen by HIV care providers and their patients. Large clinical trials comparing the Quad with some first-line favorites will help determine whether four drugs beats three.


New Screening and Treatment Guidelines for Bone Disease

A review of:
McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers [abstract].
Clin Infect Dis [serial online]. October 15, 2010;51(8):937-946. Available at: www.journals.uchicago.edu/doi/abs/10.1086/656412.

When I was a medical student doing rounds, the chief resident in orthopedics asked me what I thought was the most important organ in the body. Oblivious to the obvious, I answered, "The heart, since it pumps blood." "To the bones," he quickly replied.

While I remain skeptical of the primacy of the skeleton among all parts of our anatomy, in HIV care bones are gaining in importance. A number of studies have found the bone mineral density (BMD) of HIV-infected persons to be significantly lower than that of those without HIV, raising concerns for an increased risk of fractures.

The reasons for this relatively lower BMD among HIV-infected people remain unclear. Certainly, HIV-infected patients tend to have more risk factors for weaker bones. Call it hard living: Smoking (epidemic among people with HIV), alcohol abuse, low weight and poor nutrition can each lead to the leaching of hard minerals from bones. Many people living with HIV have also had a fair share of exposure to corticosteroids, such as prednisone (Prednisone Intensol, Sterapred), which is another risk factor. Further, low testosterone and vitamin D levels -- not uncommon in HIV-infected individuals -- can lead to osteopenia and the more severe osteoporosis.

The role of antiretrovirals in low BMD is more complex. Longitudinal studies in which patients were followed after they initiated HIV therapy have consistently found dramatic, immediate reductions in bone density. Specifically, BMD losses of 2% to 6% over the first two years of therapy have been observed -- a rate similar to the loss seen during the first couple of years after menopause. This effect does not appear to be specific to any one antiretroviral or regimen. That said, tenofovir use does lead to deeper declines in BMD compared to other drugs in its class. Fortunately, the nose dive in BMD with this and other antiretrovirals begins to level out after a time, at which point it declines at a more measured pace.

What to do about all of this bone loss has been unclear. Without a rash of broken bones among HIV-infected people to spark action, there has been little enthusiasm for screening and treatment of low BMD in this population. But now, with a new focus on aging and HIV, bone health is earning some respect. Capitalizing on this attention, a group of experts has issued a set of recommendations outlining who among those with HIV should be screened and treated for low BMD.

According to the recommendations, the following HIV-infected individuals should undergo dual-energy X-ray absorptiometry (DXA):

  1. Post-menopausal women.
  2. Men 50 years of age or older.
  3. Patients who have a history of fragility fracture (a fracture resulting from trauma that is less than or equivalent to a fall from a standing position), regardless of age or sex.

Those with a T-score that is more than one standard deviation less than normal (i.e., T-score = -1) should be evaluated for a secondary cause of low BMD. A nice list of these secondary causes is included in a table within the published recommendations.

Recommendations regarding who to treat for low BMD -- and what to treat with -- are also included.

The Bottom Line

This review and the resultant recommendations provide a strong rationale for increased screening and treatment of low BMD in HIV-infected patients and breaks through an ambivalence that has surrounded this issue. Importantly, the recommendations place an emphasis on the fracture risk caused by low BMD. As HIV-infected individuals age, their relatively lower BMD, regardless of cause, is expected to increase the rate of fractures -- which will, in turn, greatly impact their quality of life. Screening with DXA, therefore, makes sense, especially when there are effective interventions to offset bone demineralization.

Clinicians respond to recommendations and guidelines, so hopefully this paper will attract their attention. Of course, there will be some pushback and issues to be dealt with. For instance, DXA scanning may not always be covered by third-party payers. Will patients be willing (or able) to shoulder the expense of the test? Also, with low vitamin D levels being the rule rather than the exception among people with HIV, it is likely that most all patients with low BMD will require vitamin D replacement therapy before anything else is done. Those with osteoporosis may eventually receive bisphosphonates such as alendronate (Fosamax). However, the long-term safety of such treatments has been called into question, and HIV clinicians will have to be careful to learn about them and understand how to use them.

Despite the hurdles, these recommendations lay on the line what those in the know think should be done. The rest of us should listen.


Tesamorelin Approved to Reverse Some Fat Gain

A review of:
Falutz J, Potvin D, Mamputu J-C, et al. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension [abstract].
J Acquir Immune Defic Syndr [serial online]. March 1, 2010;53(3):311-322. Available at: http://journals.lww.com/jaids/pages/articleviewer.aspx?year=2010&issue=03010&article=00005&type=abstract.

HIV-related body shape issues have not gone away. A significant proportion of my patients complain about an accumulation of belly fat that is disproportionate to fat gain elsewhere on their bodies. Some are just plain fat, but a number of them do have a strange distribution of adipose tissue concentrated in the deep abdomen. Other than the easier-to-say-than-to-do admonishments to exercise and cut down on the Doritos, there has not been much to offer such patients. Sure, there is recombinant growth hormone, but it carries a host of side effects (arthralgias, myalgias, pedal edema), is not indicated for fat accumulation and costs a king's ransom.

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Along comes tesamorelin (Egrifta), which triggers the release of growth hormone from the pituitary, thus producing a smoother and more physiologic increase in growth hormone levels than direct hormone injections can. The drug was approved in late 2010 by the FDA to reduce excess abdominal fat in HIV-infected patients with abdominal lipohypertrophy.

In two large, placebo-controlled clinical trials that enrolled HIV-infected patients with excess abdominal fat (with "excess" defined in men as having a waist circumference of 95 cm or greater and waist-to-hip ratio of 0.94 or greater, and in women as having a waist circumference of 94 cm or greater and a waist-to-hip ratio of 0.88 or greater), tesamorelin was found to significantly reduce visceral adipose tissue (VAT). In fact, those who used it experienced a 2-cm decrease in waist size (on average) over approximately six months.

Importantly, the drug was fairly well tolerated, with the main issues being injection site reactions, itching and myalgias. Unlike recombinant growth hormone, tesamorelin use did not result in wasting of subcutaneous adipose tissue (SAT). It did, however, increase glucose levels and levels of insulin-like growth factor 1 (IGF-1) in some people, the significance of which remains unclear. Whether the drug also will help reduce fat accumulation in other locations, such as the neck, has not been studied.

The Bottom Line

Body fat still matters, and many HIV-infected patients have had no choice but to live with their disproportionately big bellies as a sad price to pay for long-term survival. While tesamorelin will not be able to turn flab into Jersey Shore-worthy abs, for some, a reduction of a few centimeters of fat off the waist would be worth its weight in gold.

Speaking of which: At press time, it remains unclear how much tesamorelin will cost or what patient support will be made available. One hopes that those marketing tesamorelin will wisely and generously choose to extend availability of the drug to patients just like those they enrolled in their studies.


At Long Last, a Published When-to-Start Trial

A review of:
Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti.
N Engl J Med [serial online]. July 15, 2010;363(3):257-265. Available at: www.nejm.org/doi/full/10.1056/NEJMoa0910370.

There are dozens of clinical trials involving HIV medications, but precious few that look at when to start these drugs. Landmark studies for those with CD4+ cell counts below 200 cells/mm3 firmly established combination antiretroviral therapies for those with AIDS. For those with higher CD4+ cell counts, HIV treatment has been justified largely by observational cohort data rather than randomized clinical trials. In fact, there had not been a randomized trial comparing the timing of the initiation of HIV therapy for those with CD4+ cell counts above 200 cells/mm3. Until now.

The GHESKIO (Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes) research group in Haiti enrolled 816 HIV-infected, antiretroviral-naive patients with CD4+ cell counts between 200 cells/mm3 and 350 cells/mm3. The volunteers either immediately initiated HIV therapy with zidovudine, lamivudine (3TC, Epivir) and efavirenz or deferred treatment until 1) their CD4+ cell counts fell below 200 cells/mm3, 2) they developed clinical AIDS or 3) another indication for treatment arose.

More than half (58%) of the cohort was comprised of women. The mean CD4+ cell count at baseline was 281 cells/mm3 and was well balanced between the arms. Almost all participants received trimethoprim-sulfamethoxazole (Bactrim, Septra) for opportunistic infection prophylaxis and were screened for latent tuberculosis; those with a positive PPD (purified protein derivative) skin test (about a quarter of the cohort) received isoniazid (Tubizid).

Provided by Daniel Fitzgerald; reprinted with permission.

Provided by Daniel Fitzgerald; reprinted with permission.

During the course of the trial there were 29 deaths: 23 in the defer-treatment arm and 6 in the early-treatment arm (P = .001). In the Kaplan-Meier analysis, 93% in the defer-treatment group versus 98% of those in the early-treatment group were alive at 36 months. The unadjusted hazard ratio for the risk of death with deferral compared with early treatment was 4.0 (95% CI, 1.6 to 9.8). This means that the risk of death was four times greater among those assigned to delay HIV therapy. The causes of death in both arms were varied and included a host of infectious and non-infectious etiologies (including homicide, trauma and suicide). There were 17 infectious disease-related deaths in the deferral arm, but only one in the early-treatment group. There were also 36 cases of incident tuberculosis in the defer-treatment group and 18 in the early-treatment group (P = .01 by the log-rank test).

In the deferral arm, 160 volunteers (39%) eventually started antiretroviral therapy; of these, 147 had a CD4+ cell count that fell below 200 cells/mm3.

For those in the early-treatment group, 8% had a severe adverse reaction to the antiretrovirals, most commonly anemia.

The Bottom Line

Within the raging debate regarding the optimal time to start HIV therapy, the results of this trial provide the strongest data to date on the benefits of HIV therapy in the 200 cells/mm3 to 350 cells/mm3 range. While we in the medical community have been treating patients with such counts, we have done so without the benefit of a randomized trial.

Certainly, there are limitations to extrapolating these results. The study was done in Haiti and the findings have the greatest significance for the treatment of HIV in resource-limited areas. Further, many of those in the deferral arm had counts that dropped well below the 200 cells/mm3 CD4+ cell count threshold, when the risk of badness is highest.

However, the benefits of HIV therapy seen in the study jive with the findings of the large cohort studies done in North America and Europe, and endorse an earlier rather than delayed approach to the treatment of HIV. That said, as we increase the CD4+ cell count starting line beyond 200 and 350, we again find ourselves in a gap between observational studies and randomized trials. The recently launched START trial, which compares HIV therapy initiation at CD4+ cell counts above 500 cells/mm3 versus waiting until counts fall below 350 cells/mm3, will pick off where the GHESKIO study ended.


"Test and Treat": Thoughts and Afterthoughts

A review of:
Wang L, Ge Z, Luo J, et al. HIV transmission risk among serodiscordant couples: a retrospective study of former plasma donors in Henan, China [abstract].
J Acquir Immune Defic Syndr [serial online]. October 1, 2010;55(2):232-238. Available at: http://journals.lww.com/jaids/Abstract/2010/10010/HIV_Transmission_Risk_Among_Serodiscordant.18.aspx.

and

Cohen MS. HIV treatment as prevention: to be or not to be? [abstract]. J Acquir Immune Defic Syndr [serial online]. October 1, 2010;55(2):137-138. Available at: http://journals.lww.com/jaids/Citation/2010/10010/HIV_Treatment_as_Prevention__To_be_or_not_to_be_.1.aspx.

The "seek, test and treat" (TnT) model aims to reduce the spread of HIV by identifying those who are unaware they are HIV infected and offering them HIV treatment to reduce their infectiousness. The approach received considerable attention last year, and continues to go strong as 2010 comes to a close. Although it is a theoretical approach rather than a proven method to reduce new infections, TnT is nonetheless already accepted by some as tried-and-true. True, it may be. Tried? Not really.

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Only now are efforts to implement TnT strategies underway and the immediate impact being examined. Pilot projects in Washington, D.C., and the Bronx in New York City have been put in place to increase HIV testing of the populace. Regarding the former, a presentation at the 17th Conference on Retroviruses and Opportunistic Infections in February 2010 reported a dramatic increase -- numbering in the tens of thousands -- in the number of Washingtonians tested, as well as a 17% jump in HIV diagnoses from 2006 to 2009. Importantly, CD4+ cell counts of those found to be HIV infected also rose to more than 300 cells/mm3, demonstrating the ability of expanded HIV screening to find people earlier in the course of their disease.

However, determining whether early testing and more aggressive treatment of HIV lead to fewer infections is a difficult thing to measure. It is notoriously challenging to capture true HIV incidence data; studies that look at new diagnoses within a given community usually just reflect transmissions that occurred years ago, rather than the leading edge of the epidemic.

While the potential benefits of TnT -- early case finding and the administration of behavioral and medical interventions to reduce infectiousness -- are highly compelling, the absence of a demonstrated impact on HIV transmission and the practical challenges for scale-up of TnT have led to concerns and calls for caution.

In the "concerns" column is the prospect of TnT causing an increase in antiretroviral resistance. Broader application of antiretroviral therapy -- which would include those who may adhere as poorly to HIV therapy as they do to condoms -- can potentially lead to cultivation and then transmission of resistant virus, this argument warns. It's unclear whether this would be offset by a reduction in viral load and less overall transmission. There is also a separate issue of cost, which may not be trivial even if the approach is cost-effective overall.

Caution is urged by others who point to an under-appreciation of the limits of TnT. There is a differential concentration of antiretrovirals into the genital tract, which means there is a potential disconnect between HIV viral load in the blood plasma and HIV viral load in genital secretions. Further, even when antiretrovirals are present in these compartments, HIV may not be reliably suppressed. Therefore, in some people, on some regimens, there may remain sufficient virus in the semen or cervico-vaginal fluid to permit HIV transmission.

As is made clear from reports of transmission of HIV by individuals who are being treated with potent antiretrovirals, HIV therapy does not render all people incapable of passing along their virus. In a real-world application, 84 HIV transmission events were noted among a group of 1,927 couples in China who were followed from 2006 through 2008, and these transmission events were equally distributed among patients who were receiving and those who were not receiving HIV therapy. Problems with adherence to medications, incidence of other sexually transmitted diseases or HIV infection from another partner may explain these infections, but such explanations are a part of life. They may reflect the limits of what TnT can accomplish outside of the clean inputs of computer models.

Lastly, there are some data suggesting that a disproportionate amount of HIV transmission comes from those with acute or early infection. TnT does not reach these newly infected patients, who may well be considered hyper-infectious.

The Bottom Line

The enthusiastic embrace of TnT, fanned by modeling studies that help us to envision a world without AIDS, is understandable. But as the gleam of the idea of TnT begins to pass, it is wise to consider the practical aspects of the strategy. Those of us who believe data and experience support earlier use of antiretrovirals can also push for increased attention to the development of evidence-based and scalable interventions to support medication adherence and deal with factors that threaten suppression of viremia, including substance abuse and mental illness.

A wise man (OK, Dr. Myron Cohen, the guy who signs my paychecks) once said, "We cannot treat our way out of the HIV epidemic." Dr. Cohen is right, but the question is: Can we use HIV therapy, despite its limitations, thoughtfully to prevent thousands of infections? Let's find out.


Republicans Sweep the House and Rattle the Senate

The results of the 2010 mid-term elections in the U.S. will have an effect on issues you care about, regardless of whether you are red or blue, triumphant or disheartened. The 2011 Congress will likely determine what stays and what goes from the President's health care overhaul, which will have ramifications for health care coverage and clinician reimbursement.

Perhaps even more important is how the elections played at the local level: Many state legislatures and governorships moved to the right, and it is these policy-makers who may have the greatest impact on how clinical care will be delivered to persons living with HIV.

Predicting what will happen in health care policy over the next year is for fools and pundits. Regardless, the elections, like all elections of late, were important. Thus, although I list it last, it is hardly the least important clinical development of the year.


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