A STEP Conference Report
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.
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.
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:
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.
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.
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.
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.
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.
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:
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.)
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.
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.
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.
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.
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.
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.
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.
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.
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.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.