Coverage of the 5th Conference on Retroviruses and Opportunistic Infections
February 1 and 2, 1998
Opening Session Highlights
Dr. Ashley Haase delivered one of the two opening addresses. He reviewed the data that shows that the lymph nodes remain the main reservoir of HIV after HAART therapy. The lymph nodes contain lymphocytes with no viral RNA, but with viral DNA incorporated into their genetic code. He referred to the M "mystery" cells that harbor HIV DNA. These cells persist in the lymph nodes even after two years of no detectable plasma HIV on HAART. Thus, the realization over the last 6 months that HAART will probably not lead to viral eradication. On a more positive note, he noted that there is evidence of rehabilitation and rebuilding of the immune system on HAART, and that even after only 6 months of HAART, there is evidence of restoration of normal lymph node architecture.
Dr. David Baltimore delivered the Keynote Lecture, discussing the challenges of making an HIV vaccine. He is Head of the Government's AIDS Vaccine Research Committee (AVRC). Vaccines work by generating antibodies, generating cellular immunity (cytotoxic T-lymphocytes (CTL)), and/or some undefined third non-immunologic mechanism. He suggested that the third process could be that a non-pathogenic virus occupy a space need by HIV to establish infection, thus blocking infection by HIV. He noted that it is rare for a person to become infected with a second strain of HIV once they are infected with one strain of HIV. He also stated that he believes there is total commitment on the part of the Federal Government to expend whatever resources are needed to develop an AIDS vaccine. The vaccine need not necessarily prevent HIV infection, but rather prevent disease caused by HIV. It must be very safe, well tolerated, durable, transportable, easily admitted, and protect against different routes of infection, i.e. mucosal or by injection.
Dr. Baltimore noted that the Macaque monkey can be completely protected by a live SIV virus, which is deficient in a regulatory gene, the NEF gene. It has been shown that a few people in the US and Australia have been infected with a nef deficient strain of HIV and they have normal immune systems after long-term infection.
There are seven types of HIV vaccine strategies; recombinant subunits (antibodies), live vectors (CTL, i.e. poxvirus), peptid epitopes, pseudovirions, DNA immunization, whole-killed virus, and live-attenuated virus (i.e. nef deficient). He reviewed the limitations of antibody vaccines, which do not immunize against wild type (real world) virus. There is cell-mediated killing of HIV-infected lymphocytes. The half-life of HIV-infected T cells is about 2-3 days. However, one of the challenges is to figure out how HIV blocks CTL killing of infected cells. Dr. Baltimore is not in favor of giving a live-attenuated HIV virus to human volunteers, and feels that there needs to be a much better understanding of how HIV can be prevented by the various techniques discussed above.
Monitoring the Epidemic of HIV/AIDS in the United States
Session 2: State-of-the-Art Lecture
Presenter -- Kevin Decock, CDC
Summary by Jeffrey Schouten, M.D.
Seattle Treatment Education Project
The presentation reviewed the epidemiology of HIV/AIDS in the US. The major points emphasized were that transmission is closely linked the following factors; socioeconomic status, substance abuse, drugs exchanged for sex, and the increased rate of HIV transmission when other sexually transmitted diseases (STDs) are present. He noted some very concerning data from public health clinics that showed that HIV-positive persons had an STD incidence of 8/100 person years. STDs increase the risk of HIV transmission by 4-5 fold. He emphasized that better control of substance abuse and STDs is critical to control the spread of HIV. In 1997, there was a 12% decrease in incidence of AIDS compared to 1996. Dr. Decock reviewed a slide which showed the flow of HIV into one bucket, representing HIV cases, then flow into a second bucket, AIDS cases, then flow out of the second bucket to account for AIDS deaths. With decreasing AIDS cases, the number of people in the first bucket, HIV cases, is increasing. This was his justification for the CDC's call (a "technical opinion") for mandatory names reporting. He noted that 31 states require HIV names reporting, but these states represent only 1/3 of all HIV cases. He said that there have been no breaches of confidentiality. [Apparently, he is not aware of the major breach in Florida. Additionally, he did not even mention the option of unique identifiers to gather the same data, while better protecting confidentiality and not discouraging HIV testing. Editorial Comment, not reflecting anyone's view but this author.]
This session reviewed data concerning the quality of the increased T cells in people on HAART. The big question is whether or not the increased T cells are only memory cells (already programmed to respond to one antigen, or pathologic organism), or are there increases in naive T cells (new T cells capable to responding to a new pathogen, or disease causing organism). The good news is that there appears to be increases in both memory and naive T cells in people on HAART therapy. The memory cells increase in the first few weeks, then plateau (usually at 300-400), while the naive cells slowly increase over several months.
There was a great deal of detailed biochemistry presented about the chemokines. Only a few of the major concepts presented will be discussed here. There are two general classes of chemokines, C-C, and C-X-C class. There are 9 identified C-C receptors, and 4 C-X-C receptors. The chemokine receptors appear to be necessary for the HIV to bind to the CD-4 lymphocyte and infect the cell. Generally, the CXCR4 receptor is on the T cell, and the CCR5 receptor is on memory cells. The chemokines became a major focus of HIV research in the last 2 years when they were identified an important coreceptors allowing for HIV entry into the cell. Additionally, it has been shown that people with a genetic mutation resulting in no CCR5 receptors are immune to HIV infection (called the delta 32 allele). Also, people who lack one, but not both genes for the CCR5 receptor, appear to have a slower rate of disease progression. DR Moore explained why there have been some apparently conflicting data concerning the rate of progression of HIV disease in the heterozygous CCR5 population (lacking one, but not both genes which code for the CCR5 receptor). Studies which have followed progression from time of diagnosis have shown a slower rate of progression. However, studies which look at the number of heterozygous people at one time during the course of the infection, not at the initial time of infection, have not shown a difference in rate of infection. This is because the effect on disease progression is not that strong, so you will only observe the effect if you follow patients from the time of diagnosis. Another recently identified chemoreceptor is the CCR2, which also interacts with HIV binding, and genetic variants may also effect progression of HIV, possibly by influencing the expression of the CCR5 receptor on the cell surface.
The first slide session I attended this morning was Session 5 "Antiretroviral Chemotherapy I," which provided the first look at data on antiretroviral agents. The first three presentations focused on combinations that would no longer be recommended when following the new treatment guidelines but could provide information that would be useful when choosing two reverse transcriptase (RTI) inhibitor drugs to be used as part of a triple combination.
Daniel Kuritzkes MD, of the University of Colorado, presented data from the ACTG 306 study When this trial began (Dec 95) there was some question as to whether 3TC had a unique relationship with AZT or whether the same benefit could be seen when 3TC was added to ddI or d4T. To determine this, people where randomized into groups who received d4T alone, d4T/ 3TC, AZT/ 3TC, ddI alone, ddI / 3TC or AZT/ 3TC. At 48 weeks in this particular group of people, the results suggest that the combination of 3TC and d4T is at least as effective as 3TC and AZT. It was also shown that d4T/3TC was more potent than d4T monotherapy, big surprise I think we have known that for a while. The study also showed that 3TC when added to ddI is not more potent than ddI monotherapy. Dr. Kuritzkes made a point of stating that 3TC can be combined with either d4T or AZT but that the two drugs should be used as part of a combination that includes a protease inhibitor.
Now that we are convinced that 3TC can be used successfully with d4T, what about d4T plus AZT. I have long been under the impression that d4T and AZT should not be used in a combination because they were antagonistic (when taken together, you see less benefit than you would by taking either one alone). Dr. Havlir presented the results of ACTG 290 that looked to determine if AZT and d4T were antagonistic. After looking at 144 people (all who had been on AZT before) who were randomized into groups receiving AZT/d4T, d4T alone, AZT/ddI or ddI the investigators came to three conclusions. First, AZT/d4T should not be used in combinations because, AZT/d4T does not have a more potent antiviral effect than d4T monotherapy, and AZT/d4T is associated with a drop in CD4 cells in people who have taken AZT before. Second, ddI produces a greater level of viral suppression than d4T when taken by people who have used AZT previously. Third, the combination of AZT/ddI in people who are AZT experienced had no more benefit than ddI monotherapy.
Next was a presentation that actually looked at a new compound, abacavir (1592, an RTI) in combination with five different protease inhibitors. John Mellors MD, from the University of Pittsburgh, presented the results of a study that randomized 80 people into groups that received abacavir (300mg every 12 hours) in combination with either Indinavir (Crixivan), Ritonavir (Norvir), Saquinavir (Fortavase), Nelfinavir (Viracept) or the new protease inhibitor, 141W94 (1200mg every 12 hours). The drugs performed well with 50-85% of the participants below 400 copies of the virus at 16 weeks, and 40-70% below 50 copies at 16 weeks (Dr. Mellors noted that the arm containing saquinavir produced inferior results). Some participants developed a rash from abacavir (2-5%) that was seen 3-42 days after beginning therapy. It is important not to re-start abacavir after discontinuing the drug (rechallenging) because of the development of a rash. Five people were hospitalized and one person died after they were rechallenged with abacavir.
What does the future of dual protease therapy look like? Today Dr. Eron from the University of North Carolina presented a humorous and informative piece on dual protease therapy that evaluated amprenavir (141W94) with one of three other protease inhibitors: indinavir, saquinavir, and nelfinavir. Although the data presented was only for a very small group of people, 16, it helps to provide an idea of which combinations should be studied in larger trials. After 16 weeks, all participants had viral loads below 400 copies. Dr.Eron concluded by stating that the regiments were well tolerated and this study suggests that dual protease inhibitor therapy is a viable alternative to triple combinations. It seems a bit too early to compare these regiments to triple therapy, considering that no ultrasensitive viral load was presented (tests that detect virus below 400 copies) and the short study period.
In a welcome addition to the hundreds of presentations and posters, there was a varied assortment that addressed treatment issues specific to women. Although a few studies presented data on trials designed to assess the effect of anti-HIV drugs on women, most of the research being conducted continues to look at the effect of antiretroviral or prophylactic therapy on pregnant women and their newborns. While methods for reducing the risk of perinatal transmission are still an extremely important and essential area of investigation, it would be refreshing if researchers took a more serious interest in improving the health of HIV-positive women, regardless of their childbearing capabilities. The Women's Interagency HIV Study (WIHS) is one of the few, large-scale studies which focuses on women's health, and to their credit, several pharmaceutical companies are beginning to enroll women in trials to evaluate drug efficacy in women.
Session 8: AIDS Malignancies. In a symposium on AIDS malignancies, Dr. Lowy emphasized that cervical cancer is the number two cancer among women worldwide. This high incidence of cervical cancer appears to be directly related to infection with human papillomavirus (HPV), a very common STD. Researchers have found that HPV DNA is found in almost all cases of cervical cancer. In women with HIV infection, cervical HPV is more persistent than in negative women, and there is a higher proportion of cervical intraepithelial neoplasia in positive women. Further, increased rates of progression to severe dysplasia have been noted in women with HIV infection, with lower CD4+ cell levels associated with greater risk. In Abstract 258, CD4+ cell count was found to be an inconsistent predictor of HPV disease, but plasma HIV RNA levels greater than 10,000 copies posed a greater risk for oncogenic HPV.
Poster 207: Quantitative HIV-1 RNA and Other Factors Associated with Survival in the Women's Interagency HIV Study (WIHS). The objective of this ongoing study is to determine factors associated with survival in HIV infected women. To date, data has been analyzed for 2058 HIV+ and 567 HIV uninfected women recruited in five US cities from 10/94 to 10/95. Clinical, virologic and immunologic evaluations were performed every six months. There were 242 deaths in the l890 HIV+ women: low CD4+ cell count and high viral load were contributing factors, as well as the occurrence of an AIDS-defining illness. There was a trend toward poorer survival in older participants, but survival was not associated with race/ethnicity or route of HIV exposure. Thus, women with CD4 counts500,000 had the greatest risk of death.
Greetings from Chicago and the 5th Conference on Retroviruses and Opportunistic Infections. What follows is a report on three poster presentations from the Monday session of the Conference. I chose these posters for review because they're clinically important.
The median time to AIDS in patients taking a multivitamin was 71 weeks compared to 33 weeks for those not taking one. Even more striking was the AIDS-free time associated with a B complex vitamin. The median time to progression for those taking vitamin B complex was 152 weeks versus 32 weeks among those who didn't. The data were less impressive but still important for those with a diagnosis of AIDS. Median survival among AIDS patients taking vitamin B complex was 62 weeks compared to 42.5 weeks in those who did not. These results did not change even after controlling for CD4 count and antiretroviral therapy.
Since these data were obtained from a retrospective chart review and not a controlled clinical trial, it is possible that other, intervening variables influenced the results. For example, the vitamin takers may have been individuals who generally took better care of their health than the non-vitamin takers. I asked Kanter about this and he acknowledged that the vitamin takers did visit the clinic more often than their counterparts. But anyone reading this report is likely to be among people with HIV who care about their health, and may therefore benefit by taking a once a day multivitamin with the B complex vitamins in it.
Indinavir was the first choice PI for 25 (51%) of the study participants. Nelfinavir followed as the first choice of 14 (29%). Five (10%) selected saquinavir as the initial PI. One patient started on ritonavir, while four began with a combination of saquinavir and ritonavir.
At the end of 1 year, almost half of the patients, 49%, had dropped their first PI in favor of another. Of the 25 who started with indinavir, only 36% were still on it at the end of a year. Among the 64% who changed, most cited intolerance of the drug or an inability to adhere to it as the main reasons for switching. Data for the patients starting with nelfinavir was available for six months only, owing to the drug's more recent introduction to market. Of the 14 who selected nelfinavir as their first PI, 86% were still on it at six months. The three who dropped it did so due to an adverse experience, intolerance or lack of efficacy. The one patient who began with ritonavir stopped taking it because of intolerance. Four of the five who chose saquinavir as the initial PI abandoned it, with lack of efficacy as the most common reason given.
So what did patients switch to when they dropped the first PI? Thirty-nine percent rolled over to a new PI, with nelfinavir by far the most popular among those in this group (57% versus 14% for indinavir). Twenty-one percent went to the dual combination of saquinavir/ritonavir as second-line PI therapy. And twenty-nine percent took the opportunity to simply discontinue treatment. The rest selected some other form of treatment (for example, two nucelosides).
These data support the notes of caution heard in many quarters about the rigors and toxicity of PI-containing regimens. Moreover, the data underscore the importance of choosing a treatment regimen with careful attention to side effects and easy of use.
The study involved 500 HIV infected men whose CD4 cell count had fallen to 50 or below. For men in this group with viral loads of less than 100,000 median survival was 2 years; for those with viral loads between 100,000 and 250,000, 1.9 years; for those with viral loads above 250,000, 1.3 years. Interestingly, there was no discrimination in survival time between those with viral loads above 250,000 and those with viral loads above 500,000.
But for patients in each of these groups, antiretroviral therapy significantly delayed time to death. Among those with viral burdens above 250,000, treatment delayed time to death by 2.04 yrs. Among those with viral loads between 100,000 and 250,000, it delayed time to death by 2.41 years. And for those with viral loads under 100,000, treatment delayed time to death by 1.26 years. (I asked the presenter about the odd finding that survival time was shortest in those with the lowest viral load. She said this probably resulted from statistical difficulties. The number of patients in the under 100,000 group was relatively small at eleven.)
Virtually everyone would agree that the patients in this study waited too long to start treatment. Nevertheless, these data support previous findings that antiretroviral therapy provides a clinical benefit even for individuals with profound immune suppression.
This article was provided by Seattle Treatment Education Project.