Mortality Trends: Toward a New Definition of AIDS?
- Changing Patterns of Mortality
- AIDS Then and Now
- Who Gets AIDS Today?
- How Late Is Too Late?
- AIDS vs. Non-AIDS Mortality
- Shifting Causes of Illness and Death
- Liver Problems
- HPV-Associated Cancers
- HAART Risks vs. Benefits
- Changes in HIV Management
- A New Definition?
- Selected Sources
HIV disease today looks very different than it did two decades ago when the first cases were described -- at least in developed countries where highly active antiretroviral therapy (HAART) is widely available. Most HIV positive people receiving treatment no longer succumb to opportunistic illnesses (OIs) that take advantage of their ravaged immune systems. Instead, people with HIV now live longer and die from a wide variety of other causes. In other words, a growing number of positive people will die with HIV, but not of HIV.
In the HAART era, HIV positive people and their health-care providers must now think about the cumulative impact of chronic HIV infection and the long-term side effects of treatment. In addition, as effective antiretroviral therapy extends the lives of people with HIV, they become prone to conditions that normally occur with greater frequency as people age (such as heart disease, diabetes, and osteoporosis) and progressive conditions that may take decades to cause significant illness or death (such as chronic viral hepatitis). Given the shifts in the types of conditions now seen in people with HIV, it may be time to rethink the definition of AIDS.
In the 1980s and early 1990s, HIV/AIDS was a major cause of death among adults in the U.S., with the mortality (death) rate climbing every year from 1987 to 1994. By the latter year, the disease had become the leading cause of death among adults 25-44 years of age. A significant decrease in AIDS mortality first became apparent in 1996, the year after the first protease inhibitor (PI) was introduced. In 1997 the number of HIV/AIDS deaths fell by nearly 50%, followed by a further 20% reduction in 1998. By 1999, however, the decline had leveled off. According to the Centers for Disease Control and Prevention (CDC), HIV/AIDS deaths fell from more than 51,000 in 1995 to about 16,000 in 2002 (the latest year for which data are available).
In 2002 HIV/AIDS was the fifth leading cause of death for adults aged 25-44, but not in the top 15 for the population as a whole. It is important to emphasize, however, that the overall HIV/AIDS mortality rate hides differences among demographic groups. In 1996, for example, while HIV/AIDS deaths dropped by 20% among white people, the rate declined by just 2% among black individuals. The decrease among men who have sex with men was three times as great as that for injection drug users (IDUs), while the mortality rate actually rose for people infected through heterosexual contact. And in 2001 HIV/AIDS remained the leading cause of death for black women aged 25-34, compared with the third leading cause for black men, sixth for white men, and seventh for white women in the same age group.
Looking at the population as a whole, the top three causes of death in 2002 were heart disease, cancer, and stroke, followed by diabetes at number six and chronic liver disease/cirrhosis at number 12. As discussed below, these conditions now account for a growing proportion of deaths among people with HIV as well.
Perhaps the most evident change in the epidemic over the past 20 years has been the increase in the length of time people with access to good health care can expect to live after testing HIV positive or being diagnosed with AIDS. According to Dennis Osmond, PhD, of the University of California at San Francisco, in the earliest years of the epidemic individuals could expect to live about one year after an AIDS diagnosis. Survival times with AIDS began to increase in the mid-1980s as OI treatment improved. With the wider use of OI prophylaxis (preventive therapy), the time between seroconversion and an AIDS diagnosis increased as well. The introduction of PIs in 1995 -- which enabled the construction of potent combination regimens consisting of drugs from two or more classes -- led to a tremendous expansion of time between seroconversion and progression to AIDS or death. In the Multicenter AIDS Cohort Study (MACS), for example, the estimated time from seroconversion to death for a person infected at age 30 rose to a median of about 13 years by the 1995-1997 period.
Today many individuals have survived -- and even thrived -- with HIV for upwards of two decades. Because HIV/AIDS is still a relatively young disease, it is too soon to know the upper limit of survival for HIV positive people on HAART. While the long-term toxicities of antiretroviral therapy remain an urgent concern, some experts now cautiously predict that HIV positive people who receive optimal care may ultimately live a near-normal lifespan.
|How Is AIDS Defined?|
The CDC's first AIDS surveillance case definition, which went into effect in 1983, included opportunistic illnesses (OIs) most commonly seen in the first groups affected by the disease, primarily gay men. As more was learned about the syndrome, the definition was revised in 1985 and again in 1987. In 1993 the agency added new conditions to better reflect the nature of AIDS in other populations. But the biggest change that year was the addition of a CD4 cell count cutoff of 200 cells/mm3 (or CD4 cell percentage of 14%). Under this new criterion, individuals with compromised immune function could be diagnosed as having AIDS even if they were asymptomatic and had not yet developed OIs.
1987 AIDS surveillance definition for adults:
Added in the 1993 revision:
Where HAART is widely available, many people starting treatment in recent years have never reached a CD4 cell nadir (lowest-ever level) below 200 cells/mm3 or developed an AIDS-defining OI. Those who do typically fall into one of the following categories:
individuals who have been infected with HIV for a long time and may have previously received suboptimal treatment -- including nucleoside reverse transcriptase inhibitor (NRTI) monotherapy -- before the advent of HAART; such people often have HIV that is resistant to many drugs and thus have limited treatment options
people who have access to effective HAART, but either are not able to tolerate the drugs or fail to achieve adequate adherence
individuals who cannot afford antiretroviral therapy and are unable to access benefits through programs such as Medicaid or state AIDS Drug Assistance Programs (ADAPs)
people who have never been tested for HIV and do not seek care until they have already experienced significant immune system decline and perhaps developed AIDS-related symptoms.
The CDC estimates that as many as two-thirds of people living with HIV in the U.S. do not know they are infected, and nearly one-half are diagnosed after their immune function has already markedly declined. Such cases are most often seen among marginalized populations (including racial/ethnic minorities, the homeless, and IDUs) and tend to be concentrated in inner cities. Socioeconomic factors such as poverty, substance use, and coexisting psychiatric illnesses can have a profound impact on access to and success of anti-HIV therapy.
Several studies presented at the XV International AIDS Conference held this past summer in Bangkok looked at factors associated with late testing and treatment. Scott Kellerman, MD, and J. Blair from the CDC found that 1,175 of 2,063 people (57%) seen in Boston, Chicago, Hartford, Los Angeles, and San Francisco received an AIDS diagnosis within just six months of first testing HIV positive. The chances of late HIV detection were greater among African Americans (1.4 times as high as whites), Latinos/Hispanics (1.7 times as high), and individuals over age 40. African Americans were twice as likely as whites to develop AIDS before receiving antiretroviral therapy. A study from North Carolina found that late presentation was linked to male sex and living in a rural area. And an analysis of the French Hospital Database on HIV presented by Murielle Mary-Krause, MD, and colleagues showed late treatment to be associated with older age, HIV acquisition by a route other than male-to-male sex, and immigration from sub-Saharan Africa.
It is hoped that the CDC's recently announced emphasis on routine testing, along with the availability of a new rapid oral HIV test, will reduce the number of people who are unaware that they harbor HIV. Offering regular testing to individuals at risk can help bring more people into treatment earlier in the course of their disease, when antiretroviral therapy can do the most good.
Treatment of late-diagnosed individuals can be challenging, since they may require treatment or prophylaxis for OIs in addition to HAART, thereby increasing the risk of additive side effects and drug interactions. In addition, people who start HAART with low CD4 cell counts and/or high HIV viral loads remain at greater risk for progression to an AIDS-defining illness or death compared with those who start therapy with less compromised immune function.
For example, Andrew Phillips and colleagues with the CASCADE Collaboration reported in the January 2, 2004 issue of AIDS that the short-term risk of progression to AIDS rose in a linear fashion as CD4 cell count decreased and as HIV viral load and age increased. While a 25-year-old individual with 500 CD4 cells/mm3 and a viral load of 3,000 copies/mL had a miniscule 0.3% probability of developing AIDS within six months (chosen as a typical interval between clinic visits), the rate climbed to 44.8% for a 55-year-old person with 50 CD4 cells/mm3 and a viral load of 300,000 copies/mL. (For a detailed chart entitled "Predicted 6-month risk of AIDS according to age and current CD4 cell count and viral load," see the October 2004 adult U.S. federal treatment guidelines, table 3b, at http://aidsinfo.nih.gov.)
Data from the ART Cohort Collaboration illustrate the perils of late treatment. Matthias Egger, MD, and colleagues reported findings based on an analysis of some 12,500 participants in a dozen American and European clinical trials in the July 13, 2002 issue of The Lancet, and presented an update at the Bangkok AIDS conference. In this analysis, progression to AIDS or death was strongly associated with viral loads above 100,000 copies/mL and lower baseline CD4 cell counts, with risk increasing as counts fell below 350, 200, 100, and 50 CD4 cells/mm3. The rate of progression among individuals starting anti-HIV treatment with fewer than 50 cells/mm3 was five times as high as the rate among people with more than 350 cells/mm3. Starting therapy with CD4 cell counts above 350 cells/mm3 did not appreciably improve outcomes, however, lending support to the 350 cells/mm3 threshold recommended in the U.S. HIV treatment guidelines. But another analysis of the ART Cohort presented at the same conference by Caroline Sabin showed an increased risk of progression among individuals starting treatment with 200-350 CD4 cells/mm3, and other research suggests that IDUs may need to initiate antiretroviral therapy at higher CD4 counts to derive the same benefit that non-IDUs get from starting at lower CD4 cell levels (see "News Briefs" in this issue), so the question as to whether people within this range should start therapy remains somewhat murky.
Despite abundant evidence that deteriorating immune function and increasing HIV viral load levels are associated with a greater risk of progression to AIDS or death, research on the whole indicates that even people who begin treatment with severe immunosuppression, very low CD4 cell counts, high viral loads, and/or symptomatic AIDS can still derive significant benefit from antiretroviral therapy. For example, S. Koltar and colleagues reported in the November 15, 2004 issue of Clinical Infectious Diseases (CID) that in the ACTG 362 study, which included 612 participants followed for 3-5 years, HIV disease progression was uncommon (1.75 new AIDS-defining conditions per 100 person-years [PY]) in people who started HAART with CD4 cell counts below 50 cells/mm3 -- 62% of whom had previously been diagnosed with at least one AIDS-defining illness -- as long as they were then able to achieve sustained CD4 cell increases of at least 100 cells/mm3 and maintain low HIV viral loads.
Dying with HIV disease today is not the same as dying of AIDS a decade or two ago. As the number of deaths due to OIs and other AIDS-defining conditions has fallen, the proportion of deaths due to all other causes has consequently risen. Importantly, such a shift does not necessarily indicate an absolute increase in the number of non-AIDS deaths, since a rising proportion of deaths due to one cause may simply reflect a falling proportion of deaths due to another.
One of the best snapshots of the epidemic is the HIV Outpatient Study (HOPS), which monitors more than 5,500 participants at a dozen U.S. HIV clinics. A HOPS analysis published in the March 26, 1998 issue of the New England Journal of Medicine (NEJM) was the first to show a marked decline in mortality at the dawn of the HAART era. Among the 1,255 subjects then in the database, the overall death rate decreased from 29.4 per 100 PY in 1995 to 8.8 per 100 PY in mid-1997. According to an update presented by Frank Palella, MD, at the 11th Conference on Retroviruses and Opportunistic Infections in February 2004, the mortality rate was 2.2 per 100 PY in 2002 -- a figure that has been roughly stable since 1998. Between 1996 and 2002 the proportion of non-OI deaths rose from 46% to 72%. "If someone takes [HAART], they will live longer and when death occurs, it will not be due to an AIDS-related condition," Dr. Palella concluded.
Looking at a large European cohort, Amanda Mocroft, PhD, and colleagues reported in the August 16, 2002 issue of AIDS that in the EuroSIDA cohort, which includes more than 8,500 HIV positive participants, the overall death rate fell from 15.6 to 2.7 per 100 PY between 1994 and 2001. In addition, the proportion of AIDS deaths decreased by 23%, while the proportion of non-AIDS deaths rose by 32% during the same period. Similarly, Ard van Sighem and colleagues with the Dutch ATHENA study reported in the October 17, 2003 issue of the same journal that among more than 3,700 participants using HAART, HIV-related mortality decreased from 3.8 to 0.7 per 100 PY between 1996 and 2000, while non-HIV-related mortality remained constant. (This research team defined deaths related to antiretroviral therapy as non-HIV-related.)
Finally, in the October 18, 2003 issue of The Lancet, Kholoud Porter, MD, and colleagues, also with the CASCADE Collaboration, reported on a study of 7,740 participants from 22 cohorts in Europe, Australia, and Canada, categorized into three groups based on when they seroconverted: pre-1997 (when HAART was introduced in these countries), 1997-1998 (limited HAART), or 1999-2001 (widespread HAART). By 1997 the rate of AIDS-related deaths had decreased by about 50%, and by 2001 it had fallen by 80%.
A wide variety of conditions fall within the broad category of "non-OI" or "non-AIDS-related" causes of morbidity (illness) and mortality. These include age-related conditions such as cardiovascular disease and diabetes, as well as toxicities associated with antiretroviral therapy.
In Dr. Koltar's ACTG 362 cohort, five participants died of AIDS-related causes between 1997 and 2002, while five died of cardiovascular conditions and five due to liver failure related to hepatitis B or C virus (HBV and HCV, respectively). In Dr. Palella's HOPS cohort, deaths due to three major OIs -- Pneumocystis carinii (now P. jiroveci) pneumonia (PCP), Mycobacterium avium complex (MAC), and cytomegalovirus (CMV) -- declined from 21.9 per 100 PY to 3.7 per 100 PY between 1994 and mid-1997. In the 2000-2002 period the most common non-OI causes of death were liver (36%), lung (23%), cardiovascular (17%), and kidney (10%) conditions.
In a different type of analysis, Richard Selik, MD, of the CDC and colleagues examined death certificate data for all deaths in the U.S. between 1987 and 1999; results were published in the April 1, 2002 issue of the Journal of Acquired Immune Deficiency Syndromes (JAIDS). From 1995 to 1999, rates of several AIDS-defining illnesses declined, including Kaposi's sarcoma (5% to 3%), CMV (7% to 3%), HIV encephalopathy (6% to 4%), and wasting (10% to 7%). At the same time, rates of deaths due to certain non-AIDS causes rose: septicemia (blood poisoning; 9% to 13%), liver disease (5% to 12%), kidney disease (6% to 9%), and heart disease (4% to 7%). The researchers suggested that improved OI prophylaxis and treatment likely contributed to decreased OI rates, while toxicity associated with antiretroviral therapy may have contributed to higher rates of liver, kidney, and heart problems. At the 2004 Retrovirus conference Dr. Selik presented 1987-1999 death certificate data for San Francisco and New York City -- two early epicenters of the epidemic -- showing that non-AIDS deaths rose from 11% to 23% during the study period.
While most studies have shown a decline in AIDS-related mortality, proportions and absolute numbers of deaths vary considerably by locale and demographic group. At the 2001 Retrovirus conference, S. Ahmad from Chicago's Cook County Hospital presented data from a retrospective chart review of all HIV inpatient deaths between January 1998 and September 2000. This patient population was predominantly comprised of substance-using African American men. Among those who died, more than half were not receiving antiretroviral therapy and about half had CD4 cell counts below 50 cells/mm3. It is therefore not surprising that OIs remained common in this cohort, accounting for about 60% of all deaths. These results underline the importance of improving access to care and promoting early testing and treatment, especially among marginalized populations.
As the relative proportion of OI or AIDS-related deaths among HIV positive people has decreased, certain non-AIDS-defining conditions have received particular attention as important new threats for people living with HIV. Liver problems are sometimes related to antiretroviral drug toxicity, but liver damage due to chronic viral hepatitis is a growing concern as people coinfected with HIV plus HBV and/or HCV live longer thanks to HAART. But HAART itself can lead to new problems, as exemplified by the potential for increased risk of cardiovascular disease due to blood lipid (fat) and glucose (sugar) elevations associated with PI-based therapy. Trends in AIDS-defining and non-AIDS-related malignancies (cancers) are less clear, but most research indicates that HIV positive individuals face a higher cancer risk than their HIV negative counterparts. Liver problems, heart disease, and malignancies in people with HIV will be discussed in detail in the following sections.
Liver problems in people with HIV tend to fall into two categories: progressive liver damage due to chronic viral hepatitis coinfection, and hepatotoxicity (liver toxicity) associated with certain antiretroviral drugs.
In the HAART era liver disease has become a major cause of hospitalization and death among people with HIV. In the February 1, 2001 issue of CID, for example, Iona Bica, MD, and colleagues reported that during the 1998-1999 period, 50% of deaths (11 of 22) of HIV positive people at Boston's New England Medical Center were due to end-stage liver disease (ESLD), compared with 12% in 1991. In Dr. Ahmad's study of patients at Cook County Hospital (about half of whom were coinfected with HCV), ESLD was the second leading cause of mortality, accounting for 35% of deaths. And in the Women's Interagency HIV Study (WIHS), liver disease was the leading non-AIDS cause of mortality in the 1994-2000 period, accounting for about 20% of all deaths.
A similar situation exists in Europe, especially in Spain and Italy. At the Instituto de Salud Carlos III in Madrid, ESLD was responsible for 43% of deaths of people with HIV in 2000, about one-third of whom were coinfected with HCV. In the French Aquitaine cohort, HCV-related ESLD was the number one cause of mortality in the 1998-1999 period (accounting for 29% of deaths), while in the EuroSIDA cohort liver-related mortality has been a leading cause of death since 2000.
Chronic Viral Hepatitis
About one-quarter of people with chronic hepatitis B or C will experience progression to liver fibrosis (buildup of fibrous tissue), cirrhosis (scarring), and/or hepatocellular carcinoma (a type of liver cancer), a process that typically takes 10-40 years. Before the advent of HAART, coinfected individuals and those with HIV alone fared similarly, because most died of AIDS-related causes before ESLD developed. Today this picture has changed. As reported in the October 21, 2004 issue of AIDS, Maurizio Bonacini, MD, and colleagues reported that HIV positive individuals coinfected with both HBV and HCV were twice as likely to die of a liver-related cause as those with either HIV/HBV or HIV/HCV, who in turn had about twice the risk as people with HIV alone (28%, 13-15%, and 6%, respectively).
Some HIV positive people coinfected with HCV and/or chronic active HBV are more likely to progress to serious liver disease, and to progress more rapidly, than those with viral hepatitis alone. (For more on this topic, see "HIV and Hepatitis Coinfection," BETA, Winter 2003.) At a June 2002 National Institutes of Health (NIH) consensus conference on management of hepatitis C, David Thomas, MD, cited a meta-analysis showing that HIV/HCV-coinfected people had a two-fold greater risk of cirrhosis and a six-fold greater risk of ESLD than those with HCV alone. Abdul Mohsen and colleagues from King's College in London estimated that the average time from HCV infection to the onset of cirrhosis was 23 years in coinfected people, compared with 32 years in people with HCV alone.
However, much early research on coinfection was conducted before the advent of HAART. More recent studies suggest that accelerated liver disease progression may be a consequence of compromised immune function, and that HIV positive people with well-controlled HIV disease may do as well as their HIV negative counterparts. Based on a case-control study of 116 HIV/HCV-coinfected subjects and 235 individuals with hepatitis C alone, for example, Eugenia Mariné-Barjoan and colleagues reported in the November 5, 2004 issue of AIDS that liver fibrosis progressed significantly more slowly in people who had been on HAART longer and in those who had a shorter interval between presumed HCV infection and initiation of anti-HIV therapy.
Research is less clear about the impact of hepatitis C on HIV disease. A majority of studies indicate that it does not have a detrimental effect. For example, Ellen Tedaldi, MD, and colleagues reported in the February 1, 2004 CID that among a cohort of 823 HIV positive individuals, those who were coinfected with HCV did not have a higher rate of progression to AIDS than those with HIV alone.
Other research supports the opposite conclusion. In the Swiss HIV Cohort of more than 3,000 participants, HIV/HCV-coinfected individuals were more likely to develop OIs (8% vs. 5%) and more than twice as likely to die of any cause (9% vs. 4%) than those with HIV alone.
Studies more consistently show that HIV/HCV-coinfected individuals experience slower immune recovery after starting antiretroviral therapy. For example, J. Martin, MD, and colleagues determined that after two years on HAART, CD4 cell counts increased by an average of 53 cells/mm3 in coinfected people compared with 111 cells/mm3 in those with HIV alone.
Fortunately, treatment for hepatitis C has improved in recent years with the adoption of pegylated interferon (Pegasys or Peg-Intron) plus ribavirin. While coinfected individuals do not respond as well to interferon-based therapy as those with HCV alone, recent research has yielded increasingly promising results. In the APRICOT study, which included 868 coinfected individuals in 19 countries, those treated with Pegasys/ribavirin for 48 weeks had a sustained virological response (SVR) rate of 40% (62% for subjects with HCV genotypes 2 or 3; 29% for those with genotype 1, which is most common in the U.S. and is more difficult to treat). SVR refers to continued undetectable HCV viral load six months after the end of treatment. In study ACTG 5071, which included 133 coinfected subjects, the SVR rate using the same regimen was 27% (73% for genotypes 2 or 3; 14% for genotype 1). Both studies were reported in the July 29, 2004 issue of NEJM.
The French RIBAVIC study (presented at the 2004 Retrovirus conference), which included 142 participants, produced a less impressive SVR rate of 26% (43% for genotypes 2 or 3; 11% for genotype 1) using Peg-Intron/ribavirin. In the September 3, 2004 issue of AIDS, Montserrat Laguno and colleagues from Barcelona reported an SVR rate of 44% for Peg-Intron/ribavirin (53% for genotypes 2 or 3; 38% for genotype 1) in a study of 95 coinfected participants -- the highest seen to date in coinfected individuals with genotype 1.
It is unclear why the SVR rates varied so much among these four studies. ACTG 5071 included more black individuals (about 33%) than APRICOT (about 10%); blacks as a group respond less well to interferon. RIBAVIC included subjects with more advanced liver damage, and rates of dropouts and severe adverse events were considerably higher.
Most people with HIV/HCV coinfection can be successfully treated for both diseases. While not everyone with HCV needs treatment, which is indicated only if liver disease is progressing, some experts believe that coinfected individuals should receive treatment for HCV early, in light of the more rapid liver disease progression in this group.
Because people with higher CD4 cell counts respond better and are better able to tolerate the side effects of interferon, experts often recommend initiating HAART to improve immunological function before starting HCV treatment. An international consensus panel has recommended that coinfected individuals considering HCV treatment should have a CD4 cell count of at least 350 cells/mm3; HCV therapy is not recommended for people with fewer than 200 cells/mm3. On the other hand, if a person has early-stage HIV disease (with a high CD4 count and low HIV viral load) but advancing liver damage, it may be more appropriate to complete HCV treatment -- which may improve the liver's ability to tolerate antiretroviral drugs -- before starting HAART.
Hepatitis B also progresses more rapidly in people with HIV. As with hepatitis C, many people with chronic hepatitis B do not need treatment. Three drugs are currently approved to treat HBV: conventional interferon, 3TC (lamivudine, Epivir), and adefovir (Hepsera). 3TC and two experimental anti-HBV drugs -- FTC (emtricitabine, Emtriva) and tenofovir DF (Viread) -- work against HIV as well as HBV (the latter two are approved for this indication; adefovir at higher doses was a failed experimental anti-HIV agent). HIV/HBV-coinfected individuals should consider including one of these dually active agents as part of their HAART regimens, but should be aware that discontinuing these drugs can lead to worsened hepatitis symptoms ("flares").
|Healthy Liver Tips|
Drug-Related Liver Toxicity
The second important liver-related problem for HIV positive people is toxicity associated with certain anti-HIV drugs, often indicated by elevated liver enzyme (ALT and AST) levels. Among the protease inhibitor drugs, full-dose ritonavir (Norvir) is the worst offender, though the lower ritonavir doses used to boost other PIs are less likely to cause hepatotoxicity. Nevirapine (Viramune) can cause a hypersensitivity reaction characterized by liver inflammation and skin rash; this is most likely to occur in women with more than 250 CD4 cells/mm3 and men with more than 400 CD4 cells/mm3.
Several studies have shown that people with existing liver disease, including chronic viral hepatitis, are more prone to drug-related liver toxicity. Ronald Reisler, MD, MPH, and colleagues reported in the December 1, 2003 issue of JAIDS that in a cohort of 2,947 individuals receiving antiretroviral therapy, HCV coinfection significantly increased the risk of grade 4 (life-threatening) liver-related adverse effects relative to the rate in people with HIV alone. But overall, the rate of serious liver toxicity is very low, even among coinfected individuals. Nevertheless, HIV positive people taking HAART -- whether or not they have viral hepatitis -- should receive regular tests to monitor liver function.
Among the population as a whole, heart disease is the leading cause of death, and cerebrovascular disease is third. (Cerebrovascular refers to blood vessels of the brain; see "Neurological Complications of HIV/AIDS" in this issue.) Thus it is no surprise that as HAART keeps HIV positive people alive longer, they too are increasingly likely to succumb to cardiovascular problems.
Yet there is growing concern that cardiovascular disease in people with HIV is not just an expected hazard of aging, but is also linked to antiretroviral therapy itself. Long-term studies show that PIs as a class are associated with metabolic side effects that were not seen in initial clinical trials, including unfavorable blood lipid profiles (elevated triglycerides and LDL "bad" cholesterol, and low HDL "good" cholesterol), insulin resistance, and diabetes mellitus -- all of which are known risk factors for atherosclerotic heart disease (hardening of the arteries) in the general population. (For more on this topic, see "Cardiovascular Disease in People with HIV," BETA, Summer/Autumn 2002; and "Insulin Resistance and Diabetes," BETA, Winter 2004.)
Although there is every reason to expect that these risk factors will also hold for HIV positive people, it is not yet clear whether rates of heart disease and cardiovascular events such as myocardial infarction (heart attack) and stroke have increased since the advent of HAART. In Dr. Selik's death certificate analysis, heart disease had become the fifth leading cause of death among HIV positive people by 1999. In the EuroSIDA study, myocardial infarction was the second leading cause of mortality after liver disease. In the HOPS cohort during the 1993-2001 study period, individuals using a PI were more likely to have heart attacks (13 of 3,013 participants, or about 4%) than those not using this class of drugs (2 of 2,663 participants, or about 0.8%). In contrast, a retrospective analysis of the medical records of more than 36,700 HIV positive veterans by Samuel Bozzette, MD, found a small (10-20%) decrease in the rate of hospital admissions and deaths due to heart attacks and strokes since HAART became widely available.
Because events such as heart attacks and strokes occur relatively infrequently, large observational studies provide some of the most valuable data about rates of cardiovascular problems over time. One such study called D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) includes more than 23,000 HIV positive individuals at 188 clinics in the U.S., Europe, and Australia, about three-quarters of whom are on HAART.
In the November 20, 2003 issue of NEJM, the D:A:D researchers reported that between December 1999 and February 2002, 126 subjects experienced myocardial infarctions, and the risk increased with duration of antiretroviral therapy -- a 26% relative increase per year of HAART exposure. Nevertheless, at the 2004 Retrovirus conference the same group reported that the myocardial infarction rate among HIV positive individuals on HAART was "of a similar magnitude to, or somewhat higher than" the rate seen in the Framingham Heart Study, a long-term study of cardiovascular risk in the general population. Importantly, the absolute rate of heart attacks among D:A:D study participants was low: about one per 250 individuals taking HAART for four years (or 3.5 per 1,000 PY). More recently, in the September 3, 2004 issue of AIDS, the D:A:D team reported that HAART use was also associated with an increased risk of stroke and a greater likelihood that a participant would require invasive heart procedures.
In studies such as HOPS and D:A:D, traditional cardiovascular risk factors -- such as male sex, older age, smoking, and family history of heart disease -- are as or more important than HAART and its associated metabolic side effects. As such, HIV positive individuals should take the same measures to promote heart health as recommended for the general population, including maintaining a healthy weight, getting regular exercise, and quitting smoking.
HAART drug substitution may also play a role. Numerous studies have shown that switching from a PI-based regimen to one built around a non-nucleoside reverse transcriptase inhibitor (NNRTI) can improve blood lipid profiles and insulin resistance, and may even increase levels of HDL "good" cholesterol. Individuals who need the potency of a PI may consider switching to one of the newer drugs in this class -- atazanavir (Reyataz) or fosamprenavir (Lexiva) -- that are less associated with unfavorable blood lipid and glucose profiles.
If lifestyle changes do not adequately control blood lipid and glucose abnormalities, and if HAART regimen alteration is not feasible, physicians can prescribe adjunct therapies, such as statins and glitazones, for their HIV positive patients. It is important, however, to be aware of the potential for interactions between these medications and antiretroviral drugs.
|Healthy Heart Tips|
The shift in mortality among people with HIV is particularly evident when looking at malignancies. Over the past two decades, rates of AIDS-defining cancers -- Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and invasive cervical cancer -- have declined overall. Looking at about 5,400 HIV positive participants drawn from the HOPS cohort and 6,700 more from two Chicago HIV clinics, for example, Pragna Patel, PhD, from the CDC reported at the 2004 Retrovirus conference that rates of KS and invasive cervical cancer, but not NHL, decreased between 1992 and 2000. Fabrice Bonnet, MD, and colleagues found that, as a percentage of total mortality, cancer accounted for 269 of 964 deaths (28%) among HIV positive people at French hospitals in 2000, with similar proportions due to AIDS-defining and non-AIDS-defining malignancies.
In the November 1, 2004 issue of CID, Roger Bedimo, MD, and colleagues reported a decline in AIDS-related cancers, accompanied by a significant increase in non-AIDS-defining malignancies, in a cohort of more than 2,800 subjects at the University of Alabama at Birmingham HIV Outpatient Clinic. Altogether, the researchers tallied 178 new cases of AIDS-defining cancer and 60 new cases of non-AIDS-defining cancer (Hodgkin's lymphoma, skin cancer, invasive anal cancer, colon cancer, lung cancer, breast cancer, kidney cancer, and head and neck cancer). Comparing pre-HAART (1989-1996) and post-HAART (1997-2002) periods, they determined that the rate of AIDS-defining malignancies fell from 40 to 11.33 cases per 1,000 PY between the two periods, while the incidence of non-AIDS-defining cancers increased from 3.27 to 10.87 cases per 1,000 PY. In this study, both nadir CD4 cell counts (22 vs. 78 cells/mm3) and CD4 cell counts at the time of cancer diagnosis (38 vs. 277 cells/mm3) were lower among subjects with AIDS-defining cancers than among those with non-AIDS-defining malignancies.
It is not surprising that AIDS-defining cancers are linked to immune suppression, since these malignancies are associated with viruses that appear to act in an opportunistic manner: Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8) for KS, human papillomavirus (HPV) for cervical cancer, and possibly Epstein-Barr virus (EBV) for NHL. In Dr. Patel's study, people with lower nadir CD4 cell counts were also at increased risk for non-AIDS-defining malignancies, suggesting that even cancers not known to be associated with oncogenic (cancer-causing) viruses are more likely to occur when the immune system is suppressed, perhaps because immune surveillance and destruction of emerging cancers is diminished.
While immune reconstitution subsequent to anti-HIV therapy appears to lower the rate of certain malignancies, most research indicates that HIV positive people remain at higher overall risk for cancer than their HIV negative counterparts. As reported in the August 1, 2004 issue of AIDS, for example, women in the WIHS cohort had higher incidence rates of all types of cancer compared with the general population (as determined from cancer registry data).
As antiretroviral therapy keeps HIV positive people alive longer, they are more prone to developing progressive cancers associated with aging, which helps explain the increased rates of non-AIDS-defining malignancies reported by many investigators since the advent of HAART. In Dr. Patel's study, HIV positive individuals were 2-4 times more likely to develop lung cancer, 3-4 times more likely to develop malignant melanoma (a type of skin cancer), and 5-10 times more likely to develop anorectal cancer than the general population. In this cohort, the incidence of other common cancers (breast, colon, prostate) was not significantly different in the HIV positive and HIV-negative subjects, but another recent study found a higher rate of prostate cancer among older men with HIV. Because of their higher level of risk, HIV positive individuals should receive regular screening and monitoring to detect developing cancer in its early, more treatable stages.
The incidence of primary CNS lymphoma (lymphoma that originates in the central nervous system, most often the brain) has declined considerably since the early years of the epidemic, but trends for other types of NHL are less clear. Research indicates that people with stronger immune systems are less likely to develop NHL, and HAART therefore has a protective effect. At the same time, as HIV positive people live longer due to effective treatment, there is more time for lymphoma to develop. Since the arrival of HAART, the balance between these two factors has tipped in different directions in different studies.
Data more consistently show that well-controlled HIV disease and higher CD4 cell counts (current or nadir) are associated with lower rates of NHL and better response to treatment (radiation therapy, chemotherapy, or some combination of the two). Individuals with more than 350 CD4 cells/mm3 rarely develop AIDS-related lymphomas, and primary CNS lymphoma typically does not occur above 50 cells/mm3. Individuals not receiving HAART, or whose antiretroviral therapy is failing, are more likely to develop NHL and to experience faster disease progression.
Although early research showed that HIV positive people did not respond as well to NHL therapy, the availability of HAART has reduced or eliminated this disadvantage, in part because it enables the use of full-dose chemotherapy. Christian Hoffmann and colleagues, for example, reported in the July 4, 2003 issue of AIDS that good response to antiretroviral therapy independently predicted longer survival in a cohort of 203 participants with AIDS-related lymphoma. While the median length of survival with NHL was about 5-8 months in the pre-HAART era, more recent studies have yielded survival times ranging from 18 to 50 months. (For more on NHL and its treatment, see "Non-Hodgkin's Lymphoma," BETA, Summer 2003.)
Cancers of the cervix, vulva, anus, and penis are associated with oncogenic strains of human papillomavirus (HPV); nononcogenic strains cause genital and other types of warts. HPV is more prevalent and more aggressive in people with suppressed immune function, and several studies have shown higher rates of abnormal cervical and/or anal cell changes in people with HIV/AIDS. Invasive cervical cancer was added as an AIDS-defining illness in 1993, following pressure from activists who felt the old definition was not sufficiently inclusive of HIV positive women. Invasive anal cancer is not currently considered an AIDS-defining condition, but many believe it should be.
Effective antiretroviral therapy allows people with HIV to live long enough for HPV disease to progress from abnormal cell morphology (atypical squamous or glandular cells of undetermined significance, ASCUS or AGCUS) to precancerous cell changes (squamous intraepithelial lesions [SIL] or cervical or anal intraepithelial neoplasia [CIN or AIN, respectively]), and finally to invasive cervical or anal cancer -- a process that may take up to ten years.
Nevertheless, invasive cervical cancer is not common among HIV positive women in the HAART era. According to a study by L. Stewart Massad, MD, and colleagues reported in the January 2, 2004 issue of AIDS, women in the WIHS cohort had a low rate of invasive cervical cancer despite having multiple risk factors. While HIV positive women were more than twice as likely as HIV negative women to have abnormal cervical cell changes (38% vs. 17%), just one new case of frank cervical cancer was detected in a woman with HIV during the 1994-2001 observation period, for an incidence rate of 1.2 per 10,000 PY. The researchers concluded that HIV positive women have a low risk for invasive cervical cancer that is "statistically indistinguishable from that in HIV seronegative women and similar to that reported among age- and race-matched women in the general population."
In contrast, rates of anal cancer appear to be on the rise among HIV positive men who have sex with men (the group at highest risk, although the condition also occurs in women and heterosexual men). For example, Mark Bower, PhD, and colleagues reported at the Bangkok AIDS conference and in the December 15, 2004 issue of JAIDS that in a prospective cohort of 8,640 HIV positive individuals, the incidence of invasive anal cancer increased from 35 per 100,000 PY in the pre-HAART era (1984-1995) to 92 per 100,000 PY in the 1996-2003 period -- a rate more than 120 times that seen in an age- and sex-matched segment of the general population. Further, comparing the pre- and post-HAART eras, the researchers detected no difference in the overall survival rates of individuals with invasive anal cancer. This is not to say that antiretroviral therapy increases the risk of anal cancer; rather, cancer is more likely to develop as people with HIV live longer. And, unlike with KS and NHL, lower CD4 cell counts and use of HAART are not associated with decreased risk of anal cancer.
Many experts believe the disparity between rates of cervical and anal cancer in people with HIV is at least partly due to differences in medical practice. If detected early -- by means of a Pap smear, possibly in conjunction with an HPV DNA test -- SIL or intraepithelial neoplasia can be treated before it progresses to frank cancer. Women have long been advised to receive regular Pap smears (at least annually for HIV positive women), followed by colposcopy (examination of the cervix with a lighted magnifying instrument) and treatment (surgery, radiation, or chemotherapy) if abnormal cells are detected. Since the 1950s the implementation of routine Pap smears has contributed to a 75% reduction in deaths due to cervical cancer in the U.S.
Despite this excellent track record, anal Pap smears are not considered a standard part of regular health monitoring for people with HIV. Researchers are currently studying the benefits of regular anal Pap smears for men who have sex with men. Until more data are available, HIV positive gay and bisexual men should discuss anal Pap screening with their health-care providers.
|Cancer Prevention Tips|
Although hepatotoxicity, cardiovascular problems, and other long-term adverse side effects associated with antiretroviral therapy are a serious concern, it is important to emphasize that liver failure, heart attacks, strokes, and other life-threatening or fatal events are quite rare, and certainly less common than fatal OIs during the early years of the epidemic.
In Dr. Reisler's JAIDS study, HIV positive people were about twice as likely to experience severe drug-related side effects as AIDS-defining conditions. Looking at data from 2,947 participants in five CPCRA trials collected between 1996 and 2001, the researchers found that 675 subjects (11.4 per 100 PY) experienced severe grade 4 toxicities, compared with 332 (5.6 per 100 PY) who developed AIDS-defining conditions. In the French Aquitaine cohort, 11% of deaths were related to antiretroviral complications including hepatotoxicity and lactic acidosis (a symptom of mitochondrial toxicity associated with certain NRTIs), compared with 10% due to late OIs. While these figures may seem ominous, the higher incidence of drug toxicities relative to AIDS-defining illness is due to the fact that OI rates have declined so sharply, not because severe side effects have become common.
Few studies have been done comparing the relative risks of antiretroviral therapy and AIDS-defining illness. In one such analysis, Dr. Egger attempted to predict the impact of HAART-related metabolic changes on cardiovascular disease. He estimated that 10-200 people would have to be treated with HAART to produce a single additional case of heart disease. Conversely, because the risk of HIV disease progression is already so low among individuals with CD4 cell counts above 350 cells/mm3 and viral loads below 5,000 copies/mL, 100-200 such people would have to receive HAART in order to prevent one OI. Dr. Egger concluded that the risks and benefits of antiretroviral therapy vary considerably based on individual factors such as age and lifestyle. "While it's clear that the benefits of HAART outweigh the risks of [heart disease] for many patients," he said, "there are definitely some patients for whom the reverse may be true."
Amidst all the sometimes complex and seemingly contradictory data, one fact stands out: HAART has profoundly reduced the rate of OIs and other AIDS-defining conditions, while the absolute incidence of serious treatment-related toxicities remains low. Nevertheless, HIV positive people and their health-care providers should carefully consider a variety of individual characteristics and risk factors when making decisions about anti-HIV therapy (see "On the Level: Making the Decision to Start Therapy," BETA, Summer 2004).
The shift in emphasis from preventing and treating OIs to coping with side effects of anti-HIV therapy and progressive conditions associated with aging has led to some important changes in the medical management of HIV disease.
It is not yet known how long people will be able to remain on potent antiretroviral drugs, since the longest experience so far is about ten (since the advent of HAART) to 15 years (since the first NRTIs). Concern about the long-term side effects of anti-HIV therapy was part of the motivation for shifting the U.S. federal HIV treatment guidelines from a "hit hard, hit early" strategy to "wait until you need it." Thus, the recommended CD4 cell threshold for starting therapy in asymptomatic, treatment-naive individuals was reduced from 500 to 350 cells/mm3, while the viral load threshold was raised first from to 20,000 to 55,000 copies/mL, and then this past October to 100,000 copies/mL.
However, as noted previously, it is not yet clear when is the ideal time to start HAART. In the December 1, 2004 issue of CID, Dr. Palella, Scott Holmberg, MD, Kenneth Lichtenstein, MD, and Diane Havlir, MD, argued that the move toward later anti-HIV therapy has been based mainly on "sparse and limited cross-sectional data." Given the availability of newer, less toxic, and more convenient drugs, as well as emerging data indicating that starting HAART with CD4 cell counts above 350 cells/mm3 may be associated with lower mortality, better and more durable immune improvement, less drug-related toxicity, and reduced HIV transmission, the researchers suggested that a reconsideration of the shift away from early treatment is "timely and justified."
In the same issue, however, two other HIV/AIDS experts, Calvin Cohen, MD, and Brian Boyle, MD, countered that even with newer antiretroviral drugs, there remain major concerns about side effects (such as cardiovascular events, insulin resistance, and bone loss) and drug resistance, and that people who start HAART with low CD4 cell counts still experience "significant immunologic recovery" and ability to control OIs. A large international trial known as SMART is now underway to investigate the relative advantages and disadvantages of early vs. delayed therapy (see "Open Clinical Trials" in this issue).
Researchers have tried various approaches such as structured treatment interruptions to minimize time on HAART. In recent years, there has been a shift from PIs to NNRTIs as the preferred first-line therapy for asymptomatic individuals with HIV, since NNRTIs are less likely to cause metabolic side effects (although they can cause other types of adverse effects, including hepatotoxicity with nevirapine and psychiatric symptoms with efavirenz [Sustiva]). Perhaps most encouraging, new anti-HIV drugs are being developed that appear less likely to cause metabolic complications, including the new PI atazanavir. Finally, as HAART keeps people alive longer, there is more opportunity to try immune-boosting techniques such as therapeutic vaccines (see "Drug Watch" in this issue) and other novel strategies to reconstitute compromised immune function.
As the causes of morbidity and mortality among people with HIV have shifted from rapidly progressing OIs to conditions that develop slowly over the long term, HIV management has had to shift from acute to chronic care. Instead of focusing on providing potent antibiotic and antifungal drugs to quickly knock out opportunistic pathogens, physicians now must emphasize ongoing monitoring and screening for signs of HAART-related side effects and for conditions that normally occur as people age. Instead of struggling merely to survive, HIV positive people can now endeavor to thrive -- aided by good long-term health habits such as quitting smoking, eating a healthy diet, getting ample sleep, and exercising regularly.
|Important Monitoring Tests|
As HIV/AIDS has become a chronic, manageable illness for many people in areas where effective treatment is widely available, it may be time to re-examine the constellation of conditions known as AIDS. In spite of a dramatic drop in mortality due to AIDS-defining illnesses, people with HIV still succumb to so-called "non-AIDS-related conditions" that are, in fact, strongly linked to HIV infection or its treatment. Yet, despite the changing nature of HIV disease, the CDC definition is still based on CD4 cell count and the presence of various OIs. A majority of HIV positive people under competent medical care can keep their CD4 cell counts above 200 cells/mm3 and avoid OIs, unless they are resistant to many drugs. Thus, the current AIDS definition does not include many people living with HIV disease today.
This definition is not merely academic, since government entitlements and other benefits may be available only to those with a diagnosis of AIDS. It is important that HIV positive people be eligible for coverage of antiretroviral therapy before they develop symptoms, rather than waiting until they are sick enough to fall within the existing AIDS definition. Another avenue is expanding AIDS Drug Assistance Programs (ADAPs) to provide therapies for conditions that are HIV-related but not AIDS-defining, such as cholesterol-lowering medications and anti-diabetes drugs. Given the new face of HIV disease, maintaining a good quality of life and attaining near-normal longevity have become the new goals of treatment.
Liz Highleyman (email@example.com) is a freelance medical writer and editor based in San Francisco.
CASCADE Collaboration. Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naive individuals and those treated in the monotherapy era. AIDS 18(1): 51-58. January 2, 2004.
Cohen, C. and others. Antiretroviral therapy: the "when to start" debates. CID 39(11): 1705-1708. December 1, 2004.
D:A:D Writing Committee. Cardio- and cerebrovascular events in HIV-infected persons. AIDS 18(13): 1811-1817. September 3, 2004.
Egger, M. and the ART Cohort Collaboration. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. The Lancet 360(9327): 119-129. July 13, 2002.
Holmberg, S. and others. The case for earlier treatment of HIV infection. CID 39(11): 1699-1704. December 1, 2004.
Mohsen, A.H. and others. Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients. Gut 52(7): 1035-1040. July 2003.
Palella, F.J. and others. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. NEJM 338: 853-860. March 26, 1998.
Patel, P. and others. Incidence of non-AIDS-defining malignancies in the HIV Outpatient Study. 11th Conference on Retroviruses and Opportunistic Infections (CROI). San Francisco. February 8-11, 2004. Abstract 81.
Reisler, R. and others. Grade 4 events are as important as AIDS events in the era of HAART. JAIDS 34(4): 379-386. December 1, 2003.
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