Coverage of the 5th Conference on Retroviruses and Opportunistic Infections
February 3, 1998
HIV Infection: The Body Fights Back
Session 35: State-of-the-Art-Lecture
Presenter -- Bruce D. Walker, Massachusetts Gen. Hosp.
Bruce Walker, from the Harvard Medical School, presented an excellent review of his studies of the immune response to primary HIV, contrasting the immune response in a long-term non-progressor to a patient who died within 4 years of HIV infection. Additionally, he presented data on the effect of HAART therapy on the immune response to primary infection.
The data presented evaluated the immune response to HIV of a person who developed AIDS within 11 months of HIV infection, and died after 4 years of aggressive antiretroviral therapy, and compared that to the results of a patient who was infected with HIV in 1979, who, after 17 years, had no detectable viral load and 1,000 CD4 cells. Neither patient had any effective neutralizing antibodies, but there was evidence of strong cellular immunity (cytotoxic T-lymphocytes (CTL), CD8 cells that are able to kill HIV-infected T helper (CD4) cells). The response to initial HIV infection in both patients was characterized by a strong CTL response, which has persisted for 17 years in one patient, but disappeared after 3 months in the rapid progressor. CTL response can both kill HIV-infected lymphocytes, as well as produce soluble chemokines that inhibit HIV production in HIV-infected cells. In laboratory studies, a CTL response can cause a 10,000-fold decrease in HIV production. Dr. Walker studied the factors responsible for preservation of the CTL response in the long-term survivor. The critical difference found was the preservation of a T-4 (helper) cell response which is responsible for activation of the CTL response. Viral load data showed very nice correlation with the amount of the T helper response and the level of HIV RNA This is the first identified immunologic viral response that has been shown to correlate with viral load. The T helper response works by the interaction of the CD4 and CD8 cells, and a good example of how this can control, but not necessarily eliminate virus infection, is with herpes infection. A universal finding is that most people with chronic HIV infection lack any HIV-specific T helper cell response, which would facilitate the CTL response and cause HIV-infected cells to be killed.
The central defect in the immune system's response to HIV is that HIV preferentially infects activated T helper cells, which are necessary to maintain the CTL response. This understanding lead to the hypothesis that if you treated people recently infected with HIV, you could prevent the infection of activated T helper cells, and this would result in preservation of the CTL response. There have been a total of 7 patients treated by Dr. Walker's group, and after up to 11 months on HAART, all 7 patients have excellent CTL response, like the 17 year survivor. However, therapy has not been stopped in any of these patients to answer the critical question of whether or not the CTL response will be maintained. Dr. Walker also studied immune responses from a group of people, some of who had been treated soon after HIV infection, and by examining the T helper response, and the CTL response, he was able to identify all 4 people who had been treated early by their CTL response. Thus, a total of 11 people who were treated early have been studied by Dr. Walker's group and all 11 have preservation of a very strong CTL response. (The first patient treated presented with fever of 104.5, sore throat, headache, and had neck stiffness, following a recent exposure to HIV. The ELISA antibody test was negative and the viral load was 1.2 million, indicating recent infection. After initiation of HAART, the patient has strong T helper activity and no detectable HIV RNA.)
The major unanswered questions, as outlined by Dr. Walker, are as follows:
Can drug therapy be stopped after preserving the T helper response, and the resulting CTL response? This is a big unknown.
How long can you wait to start therapy after infection, and still preserve the T helper and CTL response? Probably there is a 6 month window, according to Dr. Walker, but this issue needs much more investigation.
Can HIV responses be augmented in chronically infected persons, now that HAART can block viral replication, with some type of immune modulation, such as a vaccine?
How do some people maintain the T helper response in the absence of therapy?
This was an exciting presentation, and it was reassuring to know that the immune system is capable of controlling HIV replication. Also, it demonstrates for the first time that a quantifiable immune parameter correlates with viral load. Additionally, it was nice to hear someone seriously address the possible role of immune therapy in chronically infected persons.
Beginning with an afternoon symposium and leading into the poster sessions, numerous researchers presented data on neurologic aspects of HIV disease, focusing on both opportunistic infections and levels of HIV RNA in the central nervous system.
S20: The Molecular Pathogenesis of Progressive Multifocal Leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML), which is caused by an opportunistic agent known as JC virus (JCV), occurs in approximately 5% of all AIDS cases, but infection is widespread throughout the world. The disease causes cognitive impairment and motor dysfunction. JCV targets specialized cells in the central nervous system (CNS), and while it has generally been assumed that the virus occurs only in the brain, recent evidence suggests that it may also infect lymphoid tissue and bone marrow cells. These may be the sites of primary infection in addition to the location in which JCV can reactivate before viral spread to the CNS.
Hypothetical Disease Course of PML:
S22: HIV-1 Viral Load in the CSF and Brain. This presentation asked three important questions regarding the role of HIV in cerebrospinal fluid and the brain:
Several poster presentations further substantiated the relationship between CSF viral load levels, neuropsychological impairments, HAART and survival. Interestingly, the one poster that refuted these findings, documenting two cases in which patients with PML died despite HAART, was withdrawn.
In an evening presentation to community representatives Tuesday night, clinicians and Agouron scientists presented the preliminary data on b.i.d. dosing regimens of their protease inhibitor, Nelfinavir (NFV).
Acknowledging the compliance difficulties that patients encounter when dealing with high pill burdens, the company is making an attempt to simplify combination therapy by evaluating the safety and efficacy of twice-daily dosing on NFV. Thirty-six treatment-naive patients received 1250 mg NFV + d4T/3TC or AZT/3TC, while 10 received 1000 mg NFV + AZT/3TC. At 24 weeks, it appears that 70% of the patients were undetectable below 50 copies, with most patients experiencing a 2 log drop in viral load. This very early data suggest that b.i.d. dosing of NFV is safe and durable. In a European study, patients with slightly more experienced produced similar results. Agouron cautioned that although the data are very promising, it is probably too early to make treatment changes based on these studies. Their hope is that b.i.d. dosing will improve adherence. The company also hopes to have an encapsulated formulation of NFV available by the end of the year. This is in response to complaints by patients that the large pills are difficult to swallow.
Session 49, Poster 356: Indinavir Pharmacokinetics and Menstrual Cycle Physiology. Relatively few data are available evaluating potential factors which contribute to observed variability in indinavir (IDV) pharmacokinetics (PK), particularly in women. Hormonal changes associated with the menstrual cycle (MC) and endogenous plasma cytokine (CK) concentrations may contribute to altered drug disposition. In this study, researchers obtained 8-hour PK profiles in HIV+ women compliant with IDV 800 mg q8h during various phases of the MC. IDV trough concentrations ranged from 67.5-670 nM. Considerable variability in IDV PK exist. The plan is to enroll 15 patients and to examine relationships among IDV concentrations, CK, hormones, HIV-1 RNA, & CD4 counts.
The volume of data presented at today's session was nearly overwhelming. In addition to slide presentations, I reviewed 64 posters. (When the conference ends Thursday, more than 700 posters will have been put up.) None of the information was dramatic, but quite a bit of it is both interesting and useful.
FYI: David Ho of the Aaron Diamond Center today revised his estimate of time to HIV eradication to between 5 and 20 years, depending on the number of latently infected memory CD4 cells and the rate at which they decay.
Here are the data from some of the posters I examined.
How low can you get? Session 47, Poster 326: Ultra Sensitive Detection of Plasma HIV-1 RNA for Predicting the Durability of 3-Drug Antiretroviral Therapy. This poster relates the findings of French investigators who sought to determine the prognostic value of a viral load that fell below 20 copies after 3 months of 3-drug therapy that included a protease inhibitor. Three hundred forty-nine patients, 86% of whom had taken nucleoside drugs (e.g., AZT),were included in this study. The group's median baseline CD4 cell count was 116 cells; their median baseline viral load was 5 logs.
After 3 months of treatment, 129 patients (37%) had a viral load below 200 copies; thirty-five patients (10%) came up with a viral burden of less than 20. Patients who were naïve to all antiretrovirals were most likely to get below 20. In follow up, among patients who stayed on their initial regimen, those who got their viral load to under 20 were more likely to have a durable response than those whose viral load got to under 200 but not under 20. "Virologic failure" (i.e., a viral load that rose to greater than 1000) was observed in 33% of those who initially went below 200, whereas only 12% of those who initially dropped below 20 failed.
In short, the presenters conclude that your regimen will "work" longer if you can make you viral load undetectable by the new, ultrasensitive tests that measure down to 20 copies. The findings of this study are supported by other papers, presented at this conference and elsewhere. This had led some to suggest that patients should use four or even five-drug regimens in an effort to assure that their viral loads get below 20. Maybe this is true, but such a goal is simply not possible for a lot of patients, particularly those with a history of prior treatment. Moreover, some patients would surely object to taking four or five drugs. As it is, many patients already have trouble with just three drugs. And at any rate, we know that a viral load of less than 5000 is associated with only a small risk of disease progression, particularly in those with higher CD4 cell counts.
What I'm saying is this. If you're viral load has been undetectable using the current, standard viral load assays that measure down to 500, 400 or 200 copies, and you get a viral load using the new, ultrasensitive test that comes up at, say, 150, try not to freak out. And before you decide to add or change drugs, talk this over at length with your doctor and think carefully about how such a choice might affect your future treatment options.
The Big Switch. Session 50, Poster 387: Can Nelfinavir Substitute for Other Protease Inhibitors in Persons with Plasma HIV-1 RNA Below 500 copies/ml Before the Substitution?. Some patients on indinavir or a combination of saquinavir and ritonavir are sick of the dosing demands and side effects imposed by these protease inhibitors. This had led people to wonder whether it is possible, for reasons of convience and not drug failure, to drop these protease inhibitors and switch to nelfinavir. The answer: yes, it's possible, but it's also risky.
Five physicians, headed by Cal Cohen, conducted a retrospective chart review on 53 patients taking either indinavir or saquinavir/ritonavir who elected to roll over to nelfinavir after that drug became commercially available. Most of these patients kept their background nucleoside therapy when they made the switch. At the time of the switch, all 53 patients had viral loads below the limit of detection (500 copies).
For patients who went from indinavir to nelfinavir, only 63% (5 of 8) were still undetectable after 18 weeks. For those who went from ritonavir/saquinavir to nelfinavir, only 50% (6 of 12) were still undetectable after 18 weeks. (The other 33 patients had not reached the 18 week mark at the time of analysis.) These data suggest that a high risk of treatment failure is associated with switching to nelfinavir. Since this was a retrospective chart review and not a prospective study, it is possible that the patients who "failed" after changing to nelfinavir would have failed anyway had they stay on the other protease inhibitors. Also, Joe Gathe of Houston, one of the authors of the poster, told me that so far none of the ten patients he's switched have failed. (Some of his patients were among the 33 not included in the 18 week analysis.)
The only way to know for sure whether it's okay to substitute nelfinavir for another PI would be to conduct a prospective trial, and such a study had been in the works. But one of the other authors of this paper told me that in light of these disappointing data, the manufacturer of nelfinavir has canceled the prospective study.
Is twice enough? Session 50, Poster 374: Thirty-Two Week Follow-Up of Indinavir Sulfate Administered Q8 Hours versus Q12 in Combination with Zidovudine and Lamivudine. In an effort to reduce the dosing demands of indinavir, which has to be taken three times daily on an empty stomach, the drug's maker is studying the possibility of twice daily dosing. Eighty-seven HIV positive patients, all naïve to 3TC and protease inhibitors, were randomized to receive indinavir 800 mg every 8 hours, or indinavir 1000 mg every 12 hours or indinavir 1200 mg every 12 hours. All of the patients were also given AZT and 3TC, both twice daily.
Forty-five of these patients are now out to 32 weeks. Among these patients, of those receiving the standard indinavir dose of 800 mg every 8 hours, 50% are undetectable. Among those receiving 1000 mg every 12 hours, 70% are undetectable. And among those taking 1200 mg every hours, 72% are undetectable. (The viral load test used in this study measures down to 500 copies.)
Although these numbers would seem to suggest that twice daily dosing is actually superior to the current dose of 800 mg every 8 hours, it's important to remember that these data are preliminary. Also, the company that makes the drug has not yet provided information about the plasma levels of indinavir for the patients in the 1000 mg and 1200 mg groups. However, Clinton White of the Baylor College of Medicine, one of the investigators on this study, told me that it's not yet known whether plasma levels are necessarily related to the success of the drug. He further suggested that if drug levels were relevant the 1000 mg and 1200 mg twice daily doses shouldn't have worked as long as they have, given the rapid rate at which the drug leaves the body. If these preliminary results hold up at 1 year of follow up, indinavir will become more user friendly than it is now.
The kitchen sink approach. Session 54, Poster 426: Salvage Therapy Using Six Drugs in Heavily Pretreated Patients. An Australian physician with a wonderful accent, Cassy Workman, presented data on a six-drug salvage regimen in heavily pretreated patients. Twelve patients, all of whom had failed a regimen containing indinavir, ritonavir or saquinavir, were started on the following combination: d4T 40 mg twice daily, ddI 400 mg once daily, 3TC 150 mg twice daily, nevirapine 200 mg twice daily, nelfinavir 1000 mg three times daily, and saquinavir (hard gel cap) 600 mg three times daily. It's important to note that these patients were all naïve to nevirapine and nelfinavir, but not the other drugs. The mean baseline viral load for this group was 170,065.
Of the nine patients who were able to stay on this regimen, all of them achieved viral loads below detection (400 copies) by week 12. Cassy concludes that both salvage therapy and recycling of drugs may be possible if enough drugs are used.
This article was provided by Seattle Treatment Education Project.