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A STEP Conference Report

The 8th Conference on Retroviruses and Opportunistic Infections

Spring 2001

The 8th Conference on Retroviruses and Opportunistic Infections

The 8th Annual Conference on Retroviruses and Opportunistic Infections (Retrovirus) met in Chicago from February 4-8, 2001. There were over 3,500 basic and clinical researchers, community scholarship recipients, and community press representatives from 58 countries in attendance. The purpose of the Retrovirus Conference is to bring together basic scientists and clinical researchers to facilitate translational research, moving laboratory findings into clinical trials.

Many of the lectures and symposia are available for viewing on the conference's website (www.retroconference.org). Posters and abstracts, referenced and numbered in parentheses in this report, are also available on the website.

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This year's conference highlighted the global impact of AIDS, and the lack of affordable, accessible treatment for the vast majority of people living with HIV, 90% who live in the developing world. In keeping with that emphasis, STEP will begin this conference report reviewing these issues.


The African Epidemic

The opening session included two very moving presentations, from Kevin DeCock of the Centers for Disease Control (CDC), and Jeffrey Sachs, an internationally prominent Harvard University economist. DeCock reviewed the devastating impact of AIDS in the developing world, most notably sub-Saharan Africa. He also noted the international response to Africa has been astonishingly small, asking the conference attendees to consider the following questions: What would we do if the United States faced African HIV infection rates? Are we accepting in Africa what would be unacceptable if it were in the U.S.?

Professor Sachs began his talk by emphasizing that the only missing factor for addressing the African AIDS epidemic is money. Because of severe poverty in sub-Saharan Africa, even prevention efforts, let alone HIV treatments, are out of reach. Sachs estimated that the cost of controlling the African epidemic would be only $2 billion. He pointed out that this is a "vanishingly small amount," trivial when compared to President Bush's proposed $2 trillion tax cut in the U.S. He emphasized that two to three million lives could be saved in sub-Saharan Africa with a cost of only $5 per person, per year, to developed countries.

The lack of world leadership has also hindered the process. Sachs noted that former President Clinton did not do enough for this issue, using the example of a pledge made last year to provide $10 million in U.S. aid during a presidential visit to Africa that cost $25 million. Sachs noted that Clinton could have stayed home and sent all $35 million. Another major obstacle has been the refusal of the World Bank to identify HIV treatment as a priority.

In addition, cooperation from the pharmaceutical industry is essential. For any plan to be effective, anti-HIV medications will need to be provided by the manufacturers at or near their production costs. Sachs predicted that the current lawsuits by drug companies attempting to prevent Uganda, South Africa, and Brazil from making cheap generic versions of anti-HIV drugs, as well as attempts by the World Trade Organization (WTO) to invoke sanctions against those countries, will be a public relations disaster for the pharmaceutical industry. He also expressed his beliefs that intellectual property rights (patents) should not be enforced over human rights. Sachs was optimistic that the pharmaceutical industry may be more willing to cooperate with President Bush, feeling more secure that a Republican administration will protect their U.S. markets, allowing them to maintain profits and recover research and development costs.

Sachs ended his talk with a five-fold call to action:

  1. Conduct a trial of antiretroviral therapy (ART) in Africa.

  2. Make the World Bank commit to supporting these initial trials.

  3. Make drug companies commit to providing the drugs at cost.

  4. Have developing countries agree to support the plan.

  5. Emphasize that this plan would require only $1 billion/year from the U.S.

At the closing session of the Retrovirus Conference, Dr. Anne-Valérie Kaninda, from Médecins sans Frontières (MSF, Doctors without Borders) addressed the conference and reiterated many of the above points. She also emphasized the secondary benefits of providing treatment, such as encouragement of testing, and battling discrimination and stigma. Commenting on the global response to the African AIDS epidemic, Kaninda criticized the WHO for refusing to list HIV medicines as essential medicines. Dr. Kaninda also announced that an Indian company had just agreed to make a generic three-drug antiretroviral regimen for MSF, containing stavudine/d4T (brand name Zerit), lamivudine/3TC (brand name Epivir), and nevirapine (brand name Viramune) for less than $350 a year per person. This same regimen would cost about $1,000 per year in the U.S. MSF is setting up clinics in 53 developing countries to treat HIV, but they have to rely on volunteers and have very few resources. Dr. Kaninda also noted the impossible task of deciding whom to offer treatment to when there are only enough resources to treat 1/10,000 people who need the treatment.


Epidemiology and Transmission

"Secondary" Prevention Aimed at HIV-Positive People

A new concept that is gaining momentum nationally with the Centers for Disease Control and Prevention (CDC) is the idea of developing HIV/AIDS prevention programs aimed at HIV-positive, rather than HIV-negative, individuals. A number of abstracts and discussions dealing with this topic, often called "secondary prevention," were presented at Retrovirus. In particular, one symposium explained a new CDC program called the Serostatus Approach to Fighting the [HIV] Epidemic (SAFE). This initiative promotes interventions for HIV-positive people, to prevent transmission to sexual partners. SAFE focuses on (1) testing and diagnosing all HIV-positive individuals, (2) linking people to appropriate, high-quality care and prevention services, (3) helping individuals adhere to treatment regimens, and (4) supporting individuals in reducing HIV transmission risk behaviors.


Early HIV Diagnosis Adds to Prevention Efforts

Evidence to support the idea of secondary prevention came from many abstracts. One of these dealt with the level of high-risk behaviors among people recently infected or newly diagnosed with HIV (Abstract 216). This study involved HIV-positive men and evaluated the factors associated with continued high-risk behavior. One hundred and sixteen individuals diagnosed with HIV, many during acute or primary infection were recruited within three months of their diagnosis for an interview study with two-year follow up. Sixty-two of the individuals have completed both the interviewer-administered questionnaire given at baseline and the one given at 12 months post-diagnosis. Researchers looked at changes in HIV transmission behaviors and any associations between recreational drug use and high-risk behavior.

Many participants reported reducing recreational drug use following HIV diagnosis (84% at baseline and 58% at 12-month follow up). Most also reported a reduction in the number of sexual partners. At baseline, 74% of men who have sex with men (MSM) had more than five partners in the previous six months, while only 50% reported that many partners at 12 months. For men who have sex with women, the percentage reporting more than five partners in the previous 6 months dropped from 22% at baseline to 0% at 12 months. Reductions in sex in bathhouses, sex clubs and other public sex environments among MSM also dropped (63% at baseline and 44% at 12 months).

Of the small number of participants who reported continued drug use after HIV diagnosis, there were increases in the percentage who reported that marijuana, speed or cocaine powder was their most frequently used drug (marijuana 10% to 67%, speed 10% to 30%, cocaine 4% to 16%). In MSM, marijuana use was associated with reports of sex with more than five partners in the previous six months.

The observed reductions in risk behavior among the majority of participants in the study, even in the absence of any targeted HIV prevention messages, emphasizes the importance of early HIV diagnosis as a means of preventing further transmission. The persistence of high-risk behavior in a significant proportion of respondents, however, points to the need for reinforcement of prevention messages among HIV-positive individuals. Prevention efforts could also be effective by targeting recreational drug use among MSM, which was associated with more risk behaviors.


HIV Rates and Risk Behaviors Continue to Increase Among Young MSM

Several presentations and posters at Retrovirus highlighted recent trends in HIV epidemiology. One study, in particular, received a great deal of attention from the popular press. The study, conducted by the CDC from 1998 to 2000 in Baltimore, Dallas, Los Angeles, Miami, New York and Seattle, found that the rates of HIV infection in men who have sex with men (MSM) aged 20-30 were alarmingly high (Abstract 211). In this ongoing study called the Young Men's Survey (YMS), epidemiologists surveyed more than 2,400 men at bars and other places frequented by young MSM and conducted extensive interviews. The prevalence of HIV among MSM ranged from a low of 5% in Seattle to 18% in Dallas, and there was a high level of "risky" sexual behavior in all six cities.

According to the most recent findings from YMS, 12% of MSM who were between 23 and 29 years old were HIV-positive. The incidence increased with age within this group, from 10% among 23- to 25-year-olds to 14% among 26- to 29-year-olds. The study found that among the men surveyed, 30% of African-Americans, 15% of Hispanics, 7% of non-Hispanic whites and 3% of Asian-Americans are infected with the virus.

Forty-six percent of participants said they had unprotected anal intercourse in the preceding six months. Of the 293 HIV-positive men in the study, only 29% knew they were HIV-positive before being tested as part of the study. This information has alarmed the prevention community and the CDC suspects that a substantial proportion of current HIV transmission is from people who do not know that they are infected. Although there is no direct evidence of rising HIV infections among MSM in most areas, this and earlier studies raise suspicions that such an increase may be occurring.


Evidence of Sexual Transmission of Hepatitis C Virus in a Study of MSM

Another interesting transmission issue is whether or not there is sexual transmission of the Hepatitis C virus (HCV), especially among MSM. Most transmission of HCV is thought to be through blood-to-blood contact such as needle sharing during drug use. The objective of this study was to determine HCV prevalence and identify risk factors for HCV infection (Abstract 561). This study screened for HCV antibodies in blood samples obtained from sexually active MSM in Vancouver B.C. between 1982 and 1998.

A total of 39 of the 662 participants (5.9%) were identified as HCV-positive. HCV prevalence was significantly higher among HIV-positive men compared to HIV-negative men (31/352 versus 8/310). HCV-positive men had higher numbers of male sexual partners in the previous year (more than 20 partners, 74% vs. 48%) and in their lifetime (more than 100 partners, 80% vs. 62%).

Not surprisingly, a history of injection drug use was a significant risk factor for HCV infection. However, 49% (19/39) of HCV-positive men in this study reported never using injected drugs. When these non-injection drug using (IDU) HCV-positive men were compared to other non-IDU, specific sexual practices were identified as significant risk factors for becoming HCV-positive. These were oral-anal contact and insertive fisting.


New Anti-HIV Medications

There are many potential antiretroviral drugs in development, but most are still a couple of years away from approval by the Federal Drug Administration (FDA). The nucleotide analogue reverse transcriptase inhibitor (NtRTI) tenofovir is the closest to FDA approval and manufacturer Gilead has begun an expanded access program. (See note in this issue of the STEP Perspective.) It is widely recognized that medications must be developed that are less toxic, easier to take, that work on HIV that is resistant to existing medications, or that target new sites. The expectation a few years ago was that medications that inhibit the HIV enzyme integrase would be the next class of medications to be available. However, due to unfavorable aspects of the early agents, medications in this class are only now entering the first human trials. A class known as entry inhibitors is developing much more quickly than the integrase inhibitors.

There were several presentations of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) that (at least in the test tube), appear to be effective against resistant strains of HIV. (Abstracts 11,12,13.) But these agents are only just beginning, or have not yet begun, human testing. A new PI, BMS 232632 (BMS) has the appealing characteristic that it can be dosed once a day. A study presented at Retrovirus compared three different doses of BMS (200, 400, and 500 mg), to a Viracept regimen (dosed three times a day), all combined with Zerit and Videx. (Abstract 15.) (However, because BMS is better absorbed with food, and Videx needs to be taken without food, this would not be a true once-a-day regimen.) All people in the study were treatment-naive. The 400mg dose and the 500mg dose of BMS both showed a similar ability to suppress the HIV RNA viral load to undetectable after 48 weeks. The fact that this observed HIV suppression was not better than Viracept's, however, is of concern, especially because several other available agents, including Viramune and Sustiva, have performed better than Viracept in trials with people who were nucleoside reverse transcriptase inhibitor-naive. BMS does, however, appear to have a unique resistance pattern. Trials of BMS in PI-experienced people are underway.


Entry Inhibitors: A New Class of Anti-HIV Medications

The most exciting new drugs that are moving into clinical trials are entry inhibitors. These drugs are designed to block the ability of HIV to enter cells, which is required for it to make copies of itself in the body. There are three critical steps in the entry process. The first is the attachment of a receptor on the surface of HIV, glycoprotein 41 (gp41) to the CD4 receptor on the surface of the body's cells. This triggers the second, chemokine co-receptor binding. Following this there is a critical change in the shape of the gp41 protein, leading to the third step, fusion. This complicated process allows HIV to inject its genetic message, or RNA, into the cell, and begin the process of replicating and infecting new cells.

There are many compounds now in early development that have the ability to block HIV's entry into the cell. These compounds work at different points in the above-mentioned pathway. As reported last year by Dr. Marty Hirsch, and shown in several posters at Retrovirus, these compounds have a greater effect when used together in the test tube. The compounds currently in development include an inhibitor of the CD4 receptor site on the virus (one example is PRO 542), CCR5 chemokine receptor inhibitors (such as Schering Compound C), CXCR4 inhibitors (like AMD 3100), and fusion inhibitors (including T-20 and T-1249, discussed below).

T-20 and T-1249 are very small proteins that block the fusion process. They must be injected under the skin, once a day for T-1249, and twice a day for T-20. At the Retrovirus Conference the first results of a randomized trial of T-20 were presented. (Late Breaker 5). People who had detectable viral loads on their current anti-HIV medication regimens, and who had never received an NNRTI, switched to a new regimen of Ziagen, Sustiva, Agenerase, and Norvir, plus either placebo injections or T-20 injections. All injections were twice a day, and doses of 50mg, 75mg, or 100mg were given for T-20. The only problems observed for people on T-20 were some mild to moderate discomfort at the injection site. One person did develop an injection site abscess that required medical treatment. There were 71 people in the study, and 53 had completed 16 weeks of treatment at the time of this report. The results were as follows:


16 wksAny dose of T-20Placebo 
HIV RNA <5048%37%Intent-to-treat analysis*
HIV RNA <40071%58%On treatment analysis
*This was not a true intent-to-treat analysis as the authors excluded seven people who did not get at least one HIV RNA measurement after beginning the trial. Nonetheless, T-20 appears to have improved the response rate to the new regimen in PI-experienced, NNRTI-naive people.


Further trials of T-20 are ongoing and it is anticipated that there will be an expanded access program beginning in a few months. Test tube studies have shown that it is possible to develop resistance to T-20 over time, but T-1249 and T-20 do not appear to be cross-resistant.

A different type of "entry inhibitor" was also widely discussed at the conference. This protein, called DC-SIGN, has not yet been the target of drug development (Late Breaker 10). It is a new receptor, recently discovered, which appears to allow HIV to be picked up by cells in the skin or mucous membranes, and transported to lymph nodes where it can begin to attack the immune system. There are several significant aspects to this discovery. Not only will it provide some new targets to stop HIV replication, but it also could be a very effective target to use as a topical microbicide, which could be used intra-vaginally, or intra-rectally, to prevent HIV infection. (See also, the topical microbicide article in this issue of the STEP Perspective.)


Structured Treatment Interruption: Novel Strategy or Oxymoron?

A session titled "Structured treatment interruption: Novel strategy or oxymoron?" summarized the current data on structured treatment interruptions (STI), or "supervised" treatment interruptions, as Dr. Bruce Walker prefers to call them. There were three types of interruptions described:
  1. In people who began anti-HIV therapy during acute (or primary) infection.

  2. After successful anti-HIV therapy in people with chronic HIV infection.

  3. Prior to beginning a new regimen in people with a lot of drug resistance and a failing current regimen, referred to as salvage therapy.

The first two categories are attempts to boost immune responses specific to HIV through a controlled burst of HIV replication, or auto-vaccination. The third type of interruption is used to allow non-resistant HIV, commonly called wild-type, to replace drug-resistant HIV in hopes of improving the response to the new regimen (Abstracts 288 to 293).

The only study showing significant results with STI was reported by Rosenberg and Walker in people treated during acute infection. (See the STEP E-Zine Vol. 1 Issue 16.) The usefulness of STI in the setting of chronic infection remains totally unclear, as the only data available are from small, non-randomized studies with short follow-up. All presenters agreed that people who are interested in STI should participate in ongoing, randomized, clinical trials.

Steven Deeks, from the University of California at San Francisco, presented updated information on the use of STI in the salvage setting (Abstract 292). Twenty-one people who were failing PI-containing regimens had a treatment interruption of about 18 weeks. There was a genetic shift to HIV that was sensitive to PIs in 81% of the people, and 72% showed no resistance for NRTIs. After 24 weeks on the new regimen, which included Norvir, a second PI, 2 NRTIs and a NNRTI, there was an average decrease in viral load of 1,000-fold. Even though there were significant decreases in T-cells during the treatment interruption, 68% of the people had recovered to within 90% of their baseline T-cell count after 24 weeks on their new regimen. Half of the people in this study had a new class of drug available to use in the new regimen (an NNRTI), and they all had a decrease in viral load to less than 400 copies after 24 weeks, compared to only 3 of 11 people who were not naive to any of the drug classes in their new regimen. Despite these fairly encouraging results, it is still important to emphasize that there is a risk of significant decreases in T-cell counts during treatment interruption. Also, this was not a randomized trial, so until a large randomized trial is completed that compares an immediate switch to treatment interruption with follow-up for at least 48 weeks, the efficacy of this strategy will remain unresolved.


Intermittent or Pulse Therapy

There has been increasing interest in intermittent therapy, not only as a potential immune-boosting approach, but to reduce drug side effects and the total cost of treatment. Two studies of interest were presented at Retrovirus. The first was a pilot study of 10 people who were switched from continuous anti-HIV therapy to taking their anti-HIV medications only every other week (one week on, one week off). These people all had HIV RNA viral loads below 50 copies and were on stable anti-HIV regimens before entering the trial. None of the subjects were on Sustiva, due to the concerns about the long time that Sustiva remains in the bloodstream after the subject stops taking it, which could lead to possible resistance (Abstract 354). All three of the people for whom 24-week data was available maintained HIV RNA viral loads below 50 copies after each week off of anti-HIV therapy. However, two people who delayed restarting medications for more than one week had viral rebound within two weeks.

Another study is evaluating continuous anti-HIV therapy versus cycles of two months on, one month off (Abstract 364). In this study, however, all people had viral rebound to detectable levels by the end of the monthly off cycles, and there is concern that this could lead to viral resistance over time, as well as a diminished improvement in the immune system.


The Phenomena Formerly Known as Lipodystrophy

The phenomena formerly known as lipodystrophy were redubbed "metabolic complications" at the Retrovirus conference. The long-term side effects included under this title were:
  • Elevated levels of lactate in the blood (lactic acidemia, lactic acidosis).

  • Tingling, numbness, or pain in the arms or legs (peripheral neuropathy).

  • Fat loss in the arms, legs, or face (lipoatrophy).

  • Insulin resistance or high blood sugar and/or diabetes.

  • Fat accumulation inside the abdomen (visceral adiposity).

  • Increased fat under the skin of the back or breasts.

  • Abnormal blood cholesterol or triglycerides levels (dyslipidemia).

  • Decreased bone density and other bone disorders (osteopenia, avascular necrosis).

One of the reasons that these side effects are being separated is because they appear to have distinct sets of causes and correlations. Many of these problems (neuropathy, fat loss, decreased bone density) have been observed in HIV-positive people who have never taken therapy, and seem to be caused, at least in part, by HIV infection itself. Others (lactic acidemia, drug-related neuropathy, and fat loss in the face, arms, or legs) seem to be associated with damage to an energy-producing part of human cells called mitochondria, possibly correlated with NRTI treatment. Treatment with PIs is being investigated as a contributing factor to the alterations in fat and sugar metabolism that may lead to high cholesterol and triglycerides, insulin resistance, and high blood sugar (glucose).

Because of the growing appreciation of long-term side effects, over 60 abstracts were devoted to the subject. Most studies focused on defining and finding correlations or causes rather than on treatment. Some of the factors that were examined as possible correlations, other than HIV and anti-HIV medications, were age, physical inactivity, gender, race or ethnicity, and CD4 count.


Incidence Data from MACS

Abstract 538 presented data on the incidence of fat maldistribution in men-who-have-sex-with-men (MSM) from the Multicenter AIDS Cohort Study (MACS). MACS is a long-term, observational cohort study of 5,000 MSM, both HIV-positive and HIV-negative. The study looked at the incidence of fat loss versus fat accumulation in a subset of 868 participants, (62% were HIV-positive and 38% were HIV-negative) using a survey and measurements. Because 73% of the HIV-positive men had taken "HAART" (highly active antiretroviral therapy with at least a 3-drug regimen, most including a PI) and 14% had never taken any anti-HIV medications, they also looked at differences in incidence based on anti-HIV therapy.

The results were that 25 to 35% of all the HIV-positive men had fat loss in the face, arms, or legs (lipoatrophy), compared to only 2% of the HIV-negative men. There was no statistically significant difference attributed to HIV, however, in central fat accumulation (35% of HIV-positive men versus 26% of HIV-negative men). When they looked at people who had a mixture of fat loss and fat accumulation symptoms, the differences were striking -- 40% of the HIV-positive group had mixed symptoms, compared to only 1 to 2% of the HIV-negative group. They then looked at the differences according to the type of anti-HIV therapy in this group of people with mixed symptoms. Among people who had no anti-HIV therapy, only 1 to 2 % had moderate or severe mixed symptoms. For those who had taken mono or dual NRTI therapy, 8% had mixed moderate or severe symptoms, and 20% of those who had taken HAART fell into this category.

The MACS researchers also looked at changes in blood lipids (cholesterol and triglycerides). They found that a low level of "good cholesterol" (HDL less than 35mg/dl) was associated with being HIV-positive, but did not vary with treatment history. In contrast, a high level of triglycerides (above 400mg/dl) was associated only with HAART. Another interesting finding from this data set was that the incidence of peripheral fat loss and central fat accumulation rose steadily during the first 2 years of HAART, but appeared to stabilize after that. Although this study was not randomized, it did make good use of HIV-negative and untreated HIV-positive control groups to distinguish among side effects due to HIV, those due to treatment, and those due to aging.


Lipoatrophy

Abstract 539 presented results from a small sub-study examining the differing effects of two NRTIs, Zerit and AZT, on both lipoatrophy and central fat accumulation. Both of the drugs were taken with Crixivan and Epivir for 30 months. None of the participants had ever used a PI, but a number of participants, evenly distributed between the groups, had already had mono or dual NRTI therapy with AZT, Videx or Hivid.

Similar to the MACS study, this study saw no differences between groups in central fat accumulation. The results did show a striking difference in fat atrophy. The type of fat loss, or lipoatrophy, most commonly found in people with HIV is a loss of subcutaneous (directly under the skin) fat in the face, arms, and legs. Using skin-fold measurements and physician and patient surveys, this study found that the percentage of people reporting fat loss in the face, arms, or legs after 30 months on therapy was twice as high in the group taking Zerit compared to the group taking AZT.


Looking at Lactate Levels

Many studies concerning correlations between blood lactate levels, mitochondrial damage, and other metabolic side effects were also presented. Lactate is a normal byproduct of human cells breaking down fats and sugars. Elevations in lactate levels, known as lactic acidemia, have been observed in people with HIV, especially in those taking NRTI therapy. It is also possible for a person to get "lactic acidosis," which indicates severely elevated lactate levels above 5 to 10 mmol/l and the presence of symptoms. Lactic acidosis can be a very serious, although rare, condition that often involves symptoms such as unexplained severe fatigue, nausea, and/or abdominal pain.

A summarizing lecture was given by researcher Andrew Carr of Australia. Looking at several studies presented at Retrovirus and previously, he estimated that approximately 20% of HIV-positive people on NRTI medications had mild elevations in lactate, 2 to 5 mmol/l, with no accompanying symptoms. He emphasized that routine measurements of lactate levels are not recommended, however, because these mild elevations do not appear to predict whether or not a person will progress to lactic acidosis or have symptoms.


Treatment for Peripheral Neuropathy

One of the few abstracts looking at treatment for metabolic side effects examined the use of aspirin for treatment of neuropathy (Abstract 601). Rather than having people take aspirin orally, these investigators crushed up 375 mg of aspirin, dissolved it in 7 ml diethyl ether, and applied it to the arms and legs were pain occurred. This was a rigorous, double-blind, placebo-controlled crossover study. Half of the participants applied the aspirin mixture topically, three times a day for 2 weeks, then, after a brief washout period, they switched to the placebo version (just the ether with no aspirin). The other half started with placebo and then switched to aspirin. Neither the participants nor the researchers knew which mixture was being used at any time. Throughout the study the participants assessed their level of pain relief with a survey known as the Brief Pain Inventory (BPI). When the results were unblinded, they showed that the aspirin mixture relieved pain 30% better than baseline measurements and 30% better than the placebo. In fact, some of the participants who were in the group that started with aspirin dropped out of the study when they switched to placebo because they were unwilling to give up the relief they found.


Decreases in Bone Health

Data on decreases in bone health continues to be compiled. Although the interest in HIV and bone health is fairly new, it appears that these effects have been present for some time and are just now beginning to be noticed. One of the most common effects seen and reported on is osteopenia. Osteopenia is a decrease in bone mineral density. In its most severe form, this loss of bone mineral density can lead to osteoporosis and structural fragility in the bones. Studies presented at Retrovirus estimated the prevalence of osteopenia to be 21 to 45% among people with HIV (Abstracts 626 and 629). The estimated prevalence of osteoporosis, 2 to 3%, was low, but still significantly higher than the rates for HIV-negative people of the same sex and age (Abstract 628).

Several studies also looked at a condition known as avascular necrosis (AVN). Avascular necrosis refers to the death of bone tissue, usually in the hip, due to a decrease in blood supply. Again, this condition is also very rare, but does appear to occur to a higher degree in people with HIV. A study from Johns Hopkins University (Abstract 637) found that the incidence rate for AVN of the hip among people with HIV was 48% higher than that of the general population (1.9 per 1,000 person-years compared to 0.04 per 1,000 person-years). The majority of bone health studies seemed to support the view that this is HIV related, rather than medication-related, although it is not yet entirely clear. One study (Abstract 631) did correlate osteopenia with elevated lactate levels, and possibly NRTI therapy. As with lactate levels, however, routine monitoring of bone mineral density is not yet recommended because the conditions are rare and their clinical significance is still not known. Like many of these metabolic side effects, the impact of these findings may take on more significance as the population of people living with HIV ages.

The 8th Conference on Retroviruses and Opportunistic Infections

Increases in Cardiovascular Disease Risk

Anti-HIV medications, particularly PIs, are known to increase total cholesterol, "bad" (LDL) cholesterol, and triglycerides. Before anti-HIV medications were available, it was shown that people with HIV already had low levels of "good" (HDL) cholesterol. All of these conditions increase a person's risk of cardiovascular disease. Two large studies presented at Retrovirus tried to ascertain if this increase in risk actually translates to higher levels of cardiac problems in people living with HIV.

A retrospective study in French hospitals (Abstract 657) looked at the incidence of heart attacks in people with HIV and with varying lengths of exposure to PIs. They then compared these incidences to those found in the general French population. Of 19,795 HIV-positive men who had taken a PI, there were 54 heart attacks during an 18-month period. The researchers calculated the relative risk of heart attack for people with less than 18 months of PI use, with 18 to 29 months of PI use, and with over 30 months of PI use, compared to the general population. They found that the risk was no higher for those on PIs for less than 18 months, but did increase with longer duration of PI use (1.7 times higher for those on PIs for 18 to 29 months, and 3.1 times higher for those on PIs longer than 30 months). While the findings in this study were compelling, no examination of differences in other cardiac risk factors was done, so the conclusion that PI use accounted for all the difference cannot be made.

Another large study was presented using data on patients at Kaiser Permanente of Northern California (Abstract 655). This is an ongoing, prospective observational study of coronary heart disease that began in 1996 and is following 4,500 HIV-positive and 41,000 age- and sex-matched HIV-negative people. This study found that the overall risk of hospitalization for coronary heart disease was 1.6 times higher among HIV-positive people, but that no differences in risk were attributable to PI use. These researchers did attempt to find differences in underlying cardiac risk factors by surveying the medical records of 264 HIV-positive people and 710 HIV-negative people. They found that people who were HIV-positive did tend to have higher cholesterol, but had lower blood pressure. They found no difference in rates of tobacco use or diabetes, both of which are significant risk factors.


What Can Be Done?

The growing list of known metabolic complications of HIV disease can seem overwhelming, especially because so little is known about the exact causes. The good news, however, is that a lot is known about the treatment of these conditions when they are not HIV-related. This means that there are many proven strategies that HIV-positive people can use to decrease their underlying risk. For instance, bones can be strengthened by maintaining good activity levels, supplementing calcium and vitamin D when needed, and avoiding the use of cigarettes and corticosteroids. It may also be useful to monitor and supplement hormone levels, since hypogonadism (low testosterone or estrogen levels) is a known risk factor for osteoporosis. A healthy weight and a diet including low-cholesterol, low-fat, and low-sugar foods can help control cholesterol, triglyceride and blood sugar levels. In addition, cardiac risk can be lowered by stopping smoking, exercising and using cholesterol- and triglyceride-lowering drugs, if needed.


Choosing Anti-HIV Therapy

Although very few of the symptoms show direct causation by specific anti-HIV therapies, many studies have looked at the effect of stopping or switching medications. In a few cases, stopping a given therapy is definitely warranted. One of these cases is symptomatic lactic acidosis. Lactic acidosis can require that a person interrupt the use of NRTIs and allow lactate levels to return to normal. It is also common to avoid certain PIs to attempt to control cholesterol levels. Many studies presented at Retrovirus also looked at switching from a PI to an NNRTI to alleviate metabolic symptoms (Abstracts 668-673).

These studies looked at people who had successful viral suppression (to undetectable viral loads) with a PI-based regimen, and then switched their PI for an NNRTI. In the vast majority of these studies, those who switched maintained viral suppression, suggesting that there is no negative health effect. However, few studies showed a clinically significant effect on cholesterol levels, triglycerides, or body-shape changes, such as facial and limb fat loss and central fat accumulation.





  
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This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.
 

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