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Top 10 HIV Clinical Developments of 2009

February 2010

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8. Ding-Dong the Bans Are Dead

Which old bans? The wicked bans. Two embarrassingly uninformed and harmful U.S. federal bans were lifted this year: 1) a travel and immigration restriction on those with HIV infection, and 2) a ban against the use of federal funding for needle exchange. Both were more than 20 years old and stood despite the accumulating data demonstrating neither was effective in stemming the spread of HIV.

The ban on travel and immigration was painful since it separated families, prevented HIV-infected individuals from visiting or immigrating to the U.S. and served as a national symbol of intolerance toward HIV-infected persons.

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Certainly, keeping people with HIV/AIDS out of our country did not seem to do much to prevent the incidence of HIV infection from remaining at 50,000 to 60,000 per year. The ban also restricted U.S. entry for HIV-infected scientists and advocates. As a consequence, international HIV conferences could not reasonably be held in this country. Subsequent to President Obama's order to overturn the ban, the International AIDS Society welcomed the action with an announcement that their 2012 conference will be held in Washington, D.C.

The lifting of restrictions on federal funding for needle exchange is also historic and reverses a policy rooted in a determined ignorance and blatant disregard of science. Needle exchange has been demonstrated in numerous studies -- including those conducted by or on behalf of the U.S. government -- to prevent HIV at reasonable costs without promoting injection drug use.41

The signing of the repeal by the President was met with elation by AIDS activists, HIV prevention researchers and HIV medical associations; it signaled the President's commitment to be guided by science and not simply politics.

Currently, state and local government funding, as well as private funding, support the nation's growing needle exchange programs. Millions of clean needles are being provided each year in the U.S. and it is now hoped that with the ban on federal funding lifted, eventually Washington will begin to support these programs.


The Bottom Line

It is refreshing to see common sense overcome prejudice and stupidity, although the lifting of these bans will not have much of an immediate impact.

There will be fewer hassles for HIV-infected visitors, who will not have to decide whether to lie on entry forms, and this opens a door to PLWHA wanting to immigrate to the U.S. and those waiting to apply for green cards here in the U.S.

The lifting of the needle exchange ban does not guarantee that any federal money will go to provide clean needles to anyone. However, both are important symbols of the administration's willingness to do the right thing and move beyond policies that were created in an atmosphere of fear. With these actions, President Obama has put his pen where his mouth is and as a result science wins.


9. Health Care Reform: If Not Now, When?

Some uncontested facts in the white-hot health reform debate:

  • An estimated 46 million people in the U.S. are without any health insurance and millions of others have insufficient coverage.
  • Being underinsured leads to non-urgent emergency department use and has been associated with a reduced likelihood of cancer screening and access to other preventive care measures.
  • Health care spending is rising and is currently more than 17% of the gross domestic product (GDP) compared to less than 10% for most of Europe.
  • Every other major industrial nation besides the U.S. provides health care to its population.

Most can agree that while we spend a lot on health care, we do not get a good value for our money. There is, however, less agreement on how to repair our ailing health care system. Democrats in control of the White House and Congress launched a major effort at health care reform and a voluble national debate on what health care should look like.

Reform is a herculean effort; not just the cynical amongst us doubt we will see meaningful reform. Unfortunately, due to an ineptly run senate campaign in Massachusetts, the doubters may be right and a rare and historic moment to profoundly change how health care is delivered may now be lost.

At the end of 2009 there was hope. In the span of a year, the concept of reform moved from hope and through a political caldron to be forged into bills in both houses of Congress that agree to significantly reduce the number of uninsured and bring historic changes to our system, rivaling the creation of Medicaid and Medicare.

Along the way, however, confusion has been sowed. Republicans warn of doom, while most Democrats point to the high risk of inaction. Predicted disaster for the elderly has been largely dispelled as fear mongering as has the invention of "Death Panels" by reform opponents (#1 on the "Whoppers of 2009" list put out by the non-partisan FactCheck.org).

Of course, there are legitimate concerns regarding the plans to make Medicare more efficient. The infusion of abortion into the debate has been predictable and, as intended, has stirred emotions and stalled reform. Any major legislation attracts the opportunists and protectionists, and their salvos further obscure and obfuscate.

But clarity can be found. The Kaiser Family Foundation created a side-by-side comparison of the House and Senate bills that can be tailored to specific aspects of the proposals.

The HIV Medical Association (HIVMA) has a similar comparison that highlights issues directly related to HIV. HIVMA recommendations/comments are included and generally favor the House version, which includes a national public health insurance option stripped from the Senate bill, as well as an increase in Medicaid reimbursement to Medicare levels. The association also makes its position statement on health care reform available online.


The Bottom Line

During the course of 2009, Democrats once again took up reform of our health care system and once again came up very short. They faced a Republican party that shamelessly and consistently sided with the interests of those who profit most in our current system, which includes the insurance and pharmaceutical industries.

In the Senate, a much weaker reform bill than the House version still required a 60-seat majority to avoid a certain filibuster by the Republicans who, to a senator, refused to break ranks and support a bill that would insure millions and over time reduce our federal deficit. The Democrats made costly mistakes in the horse trading that ensured their unified front, thereby drawing ire from voters. They also made a mistake by assuming they had a filibuster-proof majority. All that came to an end when the Bay State elected a republican to fill the seat vacated with the death of Senator Edward Kennedy, who was the motivating force behind the health reform movement. It's ironic that with his departure real reform also died.

For HIV care providers faced with a patient base that is challenged by poverty and other barriers to well-being, the dire need for reform has been evident. The fight is not completely over; those of us who favor reform will have to mobilize in 2010.

Physicians' organizations, including, eventually, the American Medical Association (AMA), have come around to support massive change to the health care system. The shift in the Senate calculus may mean an adjustment in our priorities. For many, the proposed reforms did not go far enough to address the inequities of care and bend too much toward the powerful special interest groups, particularly the insurance and pharmaceutical companies, who have exerted powerful influence on the bills that have emerged.

A recent New York Times article reported on how these companies have been positioning themselves in statehouses around the country to thwart any federal legislation. The American Legislative Exchange Council, a business-friendly group with a health care task force composed of government-relations officials for the Blue Cross and Blue Shield Association of insurers, Johnson & Johnson, Bayer and Hoffmann-La Roche, has been active in working at the state level to beat back reform. (If this is distasteful to you, then dear reader, please make your displeasure known to the representatives of these industries.)

While the proposed changes are not sweeping enough for those of us who favor a more universal delivery of care, and have been whittled down by special interest knives, the pragmatic recognize that what has been achieved this year is a major step in the direction of a more humane, equitable and intelligent health care system. The election in Massachusetts puts us two steps back and the fate of health care reform remains uncertain. How this cliffhanger ends will certainly be a top story of 2010.


10. The Great Recession of 2009

Last, but hardly least, is the great recession of 2009. When the economy suffers, so do people living with HIV infection. According to all surveys, a greater proportion of HIV-infected Americans live in poverty compared to the general population and many others live on an economic knife's edge even in times of plenty. How many among the millions who endured the loss of their jobs, savings and homes this year are HIV infected is not known, but it is safe to say a lot.

As HIV clinicians, we get snapshots of our patient's lives at three- to six-month intervals and this past year we heard stories of layoffs and evictions. Health insurance was scaled back or lost, and medication co-pays increased making HIV treatment unaffordable. Missed appointments were explained by an inability to afford the gas to get to the clinic.

On a larger scale, lost tax revenue led states and municipalities to deeply cut social services. In Miami, the public hospital system stopped coverage of dialysis for the indigent with end-stage renal disease -- a move that echoes a similar one made in Atlanta. Many states cut critical mental health services. With the social service safety net withdrawn, thousands fell into homelessness and swelling shelters. HIV care was not spared. In most big cities, funding of HIV/AIDS service organizations dropped.

According to the National Alliance of State and Territorial AIDS Directors (NASTAD) in Washington, D.C., about 65% of Ryan White Part B programs have reported state funding cuts for their programs and half of state ADAPs have experienced funding decreases; 55% of HIV prevention programs have experienced funding decreases in 2009.

The catastrophic meltdown of the California state economy has led to severe repercussions for HIV prevention and treatment programs and now threatens that state's ADAP. In my adopted home state of North Carolina, the once-thriving ADAP program is bust and a waiting list for new enrollees has started.

Globally, the economic crisis has led to fears of a reluctance among developed nations to honor their commitments to finance HIV prevention and treatment. Such a retreat from the advances made over the past year would immediately cost lives.

The slogan of one advocacy group, "HIV is not in recession," is as succinct as it is on target and warns us not to accept the international community's withdrawal from investing in treating and preventing HIV infection.


The Bottom Line

The gilded age of excess is over. Money is palpably scarce and there is a real possibility of things getting worse before they, eventually, get better. As the cushioning effects of the stimulus wane, the impact of the crisis will be more deeply felt. It is no surprise that PLWHA will be among those who feel it the most. HIV-infected persons in the U.S. often live deeply challenged lives and rely on public and private assistance to remain housed, in clinical care and on medication. In the midst of the worst economic crisis since 1929, these services are faltering. Several state ADAPs are broke and will default on their mission to provide HIV medications to those who cannot afford them. Lapses in HIV therapy due to an inability to pay for it, risk drug resistance and transmission of the virus to others, as well as progression of disease.

All this comes just as the DHHS guidelines have made an evidence-based recommendation to initiate therapy earlier in the course of infection.1 With the resources to pay for these drugs evaporating, it will be a struggle to cover people with CD4+ cell counts of 350 cells/mm3 or less, let alone patients with counts between 350 and 500 cells/mm3. Too bad there are no end-of-year bonuses paid to ADAPs.

Beyond the direct effects of the crisis on the supply of medications for HIV, there is concern that research entities, including the pharmaceutical industry and academic institutions, will roll back their initiatives to develop and test new antiretrovirals and conduct educational outreach, further setting us back.

There are hopeful signs of economic recovery. However, the crisis is not over yet and some worry that the glimmers of hope are the result of government stimulus initiatives that cost billions, ballooned the federal deficit and are unsustainable. These are tough times and if they get tougher, so will the lives of HIV-infected persons and those that care for them.


The Runners-Up

Suicide Rates Drop With HAART

A review of:
Suicide in HIV-infected individuals and the general population in Switzerland, 1988-2008. Olivia Keiser, Adrian Spoerri, Martin W.G. Brinkhof, Barbara Hasse, Angéle Gayet-Ageron, Frédéric Tissot, Anna Christen, Manuel Battegay, Patrick Schmid, Enos Bernasconi, Matthias Egger, for the Swiss HIV Cohort Study and the Swiss National Cohort. The American Journal of Psychiatry. December 15, 2009;167(2):143-150.

It wasn't so long ago that a diagnosis of HIV was delivered and received as a death sentence. Those on the receiving end of a diagnosis envisioned the slow wasting away that they had seen among friends and lovers. After discovering that they were HIV infected, many people planned their funerals. Some even took matters into their own hands to exert some final control over an uncontrollable infection by taking their own lives. The bleakness of HIV infection in the time before effective antiretrovirals became available was compounded by the enormous stigma associated with the disease, the isolation that often ensued and the depression that many of the infected battled.

With potent HIV therapies, there was a Lazarus-like improvement in the health of some of the sickest AIDS patients, as well as extraordinary increases in CD4+ cell counts. This has been one of the most historic and incredible reversals of disease in the history of medicine -- an event that I feel privileged to have witnessed -- and the elation among clinicians quickly spread to our patients.

However, HIV therapy is no bed of roses. Short- and long-term toxicities (such as body shape changes, neuropathy and gastrointestinal disturbances) can whittle away at a patient's quality of life. Further, although there is more tolerance and understanding regarding HIV, discrimination and stigmatization remain strong.

This analysis of mortality data from the large Swiss HIV Cohort and the Swiss National Cohort, examined the rates of suicide among HIV-infected persons in the pre-HAART (highly active antiretroviral therapy) (1988 to 1995) and the HAART (1996 to 2008) eras.42 More than 15,000 HIV-infected inmates were included -- half from the pre-HAART and half from the HAART periods. During the analysis period, there were 150 HIV-infected persons who committed suicide for a rate of 158/100,000 person-years, which is much higher than the 19/100,000 person-years observed in the general Swiss population.

Suicide declined significantly among HIV-infected persons from the pre-HAART to the HAART eras (from 447/100,000 person-years to 91/100,000 person-years). However, suicide rates also declined in the general population during this time span. For the HIV-infected patients, those enrolled in the cohort in the HAART era were more likely to be older, female, at earlier stage of disease, non-injection drug users and have a history of psychiatric treatment. More non-Swiss nationals were enrolled in the study during the HAART era than in the earlier period.

Suicide Rates in the Swiss HIV Cohort Study Compared With the General Population, 1988-2008

Click to enlarge

Adapted from Olivia Keiser et al. Am J Psychiatry. 2009;167:143-150.

The standardized mortality ratios comparing HIV-infected patients with the general Swiss population were, during the pre-HAART era, 13.7 (95% CI = 11.0 - 17.0) in men and 11.6 (95% CI = 6.4 - 20.9) in women; during the 1996 to 1998 period, 3.5 (95% CI = 1.8 - 6.7) in men and 7.0 (95% CI = 2.2 - 21.6) in women; and during the 1999 to 2008 period, 3.5 (95% CI = 2.5 - 4.8) in men and 5.7 (95% CI = 3.2 - 10.3) in women. Therefore, there were steep declines in suicide in the transition from the time before to the time after HAART became available among HIV-infected persons, although the drop was greater for men compared to women.

Risk factors for suicide in the HIV-infected and general populations included older age, being male and being a Swiss national. Injection drug use, advanced disease state and psychiatric treatment at baseline were additional risk factors for HIV-infected patients. An increase in CD4+ cell counts over time was associated with a reduced risk of suicide. Not surprisingly, there was a heavy burden of mental disease among those who committed suicide, especially among those in the more contemporaneous HAART era with 75% of those committing suicide having a mental health disorder diagnosis compared to 52% of those who committed suicide in the early era. Mental illness was mostly related to depression (as determined by surveys of the HIV providers) and most patients were reported to have been in mental health care.

A comparison of HIV data to data on other chronic incurable conditions found that suicide rates were higher for HIV-infected patients than those suffering from multiple sclerosis, breast cancer, end-stage renal disease and amyotrophic lateral sclerosis.


The Bottom Line

These are fascinating data that on the one hand show an impressive decline in suicide among HIV-infected persons in Switzerland (a country where health care and the general quality of life are pretty sweet), but on the other hand show that HIV-infected patients continue to have suicide rates that exceed those of the general population and even people living with other chronic diseases.

The study identifies a number of factors associated with suicide among those with HIV. In the pre-HAART era, HIV disease severity was found to be a driver of suicide. However, in the time of HAART, it is mental illness that was strongly associated with taking one's own life.

Three quarters of the HIV-infected people in the study who had detected mental disorders were under mental health care in the HAART era, meaning a significant proportion were not.

In addition, some cases of severe psychiatric illness, such as depression, may have been overlooked. Injection drug use was also an identified factor and while accidental overdose may lead to overestimates of suicide, the link between substance use and mental illness suggests this association is real.

Few metrics can compare with the suicide rate as a misery index. The decline in suicides among persons with HIV is a heartening indicator of the progress we have made in improving, not only the survival, but also the quality of life for people living with HIV.

But these data also show us that for many people living with HIV life is not great. Those with mental illness and injection drug use are at greater risk of suicide and also HIV infection. So, even as HIV therapy improves, the dramatic shift of the virus to people whose lives already have too little quality, challenges us to do more to recognize and treat the demons with which our patients wrestle.


The TRIO Study

A review of:
High rate of virologic success with raltegravir plus etravirine and darunavir/ritonavir in treatment-experienced patients with multidrug-resistant virus: results of the ANRS 139 TRIO trial. Y. Yazdanpanah, C. Fagard, D. Descamps, A.M. Taburet, B. Roquebert, I. Tschope, C. Katlama, G. Pialoux, C. Jacomet, C. Piketty, D. Bollens, J.-M. Molina, G. Chene. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City. Abstract THAB0406.

At only a little over 100 participants, this French study nonetheless shows us the power of Le Kitchen Sink.43

What I mean is that study after study of treatment-experienced patients has shown that the more active drugs are thrown at HIV, the better a patient's response.34,35,44,45 With the rich crop of new drugs that has popped up over the past couple of years, this is a principle that can now be put into practice.

Patients with a viral load of 1,000 copies/mL or greater while on stable HIV therapy were recruited if they were naive to raltegravir, etravirine (TMC125, Intelence) and darunavir (TMC114, Prezista); had at least three PI resistance mutations at screening, but retained susceptibility to darunavir; and had at least three nucleoside resistance mutations.

Patients were also eligible if they had a history of virologic failure while receiving NNRTI-based therapy, but were susceptible to etravirine at screening. All patients in this single-arm study were treated with raltegravir, darunavir (600 mg twice daily) plus ritonavir (100 mg twice daily), etravirine and an optimized background regimen that could include nucleosides and enfuvirtide (T-20, Fuzeon) at the discretion of the clinician.

Of the 103 patients enrolled, 88% were male. The median duration of pre-study antiretroviral therapy was 13 years. The median CD4+ cell count was 255 cells/mm3 and median entry viral load was 4.2 log10 copies/mL.

Baseline genotypic sensitivity data showed that the group had a substantial drug resistant viral burden; the median number of PI mutations (primary mutations) was four, the median number of NNRTI mutations was one and the median number of nucleoside reverse transcriptase inhibitor (NRTI) mutations was six.

Mean Change in Viral Load and CD4+ Cell Count From Baseline in the TRIO Study

Click to enlarge

Adapted from Yazdan Yazdanpanah et al. AIDS 2008; abstract THAB0406.

Two patients had three etravirine mutations and 36 patients had three primary darunavir mutations. Ninety percent of the trial participants used an optimized background along with the trio of new study medications, but only 12% used enfuvirtide.

The results were remarkable. At 24 weeks, 90% of the patients (95% CI, 85% to 96%) had an HIV-RNA level of less than 50 copies/mL. At week 48, 86% (95% CI, 80% to 93%) had an HIV-RNA level of less than 50 copies/mL. The median CD4+ cell count increase was 108 cells/mm3. In addition, the therapy was relatively well-tolerated. Only one patient discontinued therapy due to an antiretroviral adverse effect (severe rash ascribed to raltegravir) and two others decided to stop treatment unrelated to any toxicity. One patient died due to myocardial infarction during aortofemoral bypass surgery.


The Bottom Line

Treating multidrug-resistant virus with at least three active drugs resulted in excellent rates of viral suppression and CD4+ cell regeneration in this study. This is not a shocker and that is the point. When a critical mass of active and potent agents are used together, they work. The trick has been to find enough active drugs to craft a regimen. With the additions of raltegravir, darunavir and etravirine (the "TRIO" medications), as well as maraviroc (MVC, Selzentry, Celsentri) and tipranavir (TPV, Aptivus), it is now more likely that two, if not three, active drugs can be selected for an effective salvage regimen.

For many treatment-experienced patients, intolerance of medications, especially ritonavir, is at the root of their ugly genotypes. For these patients, it is challenging to identify a ritonavir-free regimen that has a prayer.

The bigger question is: Can a ritonavir-free salvage regimen work? One retrospective review of 442 patients enrolled in the U.S. raltegravir expanded access program suggests that a PI-sparing salvage regimen that includes raltegravir can lead to viral suppression rates similar to those of patients treated with a combination that includes a PI.46 Specifically, among those who took raltegravir as part of a regimen without a PI (N = 110), the viral suppression rate at 12 weeks was almost 90% -- similar to that achieved by those who took raltegravir as part of a regimen that included a PI. In both arms, as expected, the number of active drugs included in the regimen was predictive of response.

When it comes to active agents in a salvage regimen, more is better and TRIO shows us what is possible. In time, creative combinations of other new agents will be tested and if prior studies are any indication (and they are), they too will show us that we can achieve success in many patients who were considered unsalvageable.

Future research, including studies being conducted by the U.S. AIDS Clinical Trials Group (ACTG), looking at the role of retaining nucleosides in such regimens will further help us construct durable combination therapies. Meanwhile, the lesson here is don't be stingy with the salvage meds. The kitchen sink approach is worthwhile.


Conclusions

It was a tough year. It was a long year that was disappointing in many ways. The greatest economic crisis since the Depression gripped us by the money belt. Wars, costly in treasure and life, waged on. Then, with the first shoots of spring, emerged a strain of influenza that quickly blew across the planet -- igniting a pandemic of fear -- and our response became a barometer of human intelligence.

How long ago it seems now when on that brilliantly crisp January day an earnest young man held up his hand in oath. As he mouthed the words, we saw the potential for our most pressing problems to melt away. There was a real hope that our nation had decided to head in a different direction both abroad and at home -- that as a nation we were willing to right the wrongs that were long in the making.

Our elation, admittedly naive, was short-lived -- overtaken by the magnitude of the challenges we continue to face. In 2010, we will learn how well we and our leadership will do in confronting these challenges and whether, like in the preceding year, they will overwhelm progress. For the HIV care provider (and for too many patients), it will be a time of making due with less (in the clinic and at home).

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