A STEP Conference Report
Toronto: The 40th Interscience Conference on Antimicrobial Agents and Chemotherapy
The 40th ICAAC conference, the largest international meeting of infectious disease specialists, prominently featured HIV/AIDS research. Data was presented in oral presentations, poster exhibits, symposia, and state-of-the-art lectures. As at many HIV/AIDS conferences in the past year, there was evidence of incremental scientific gains and more data from ongoing studies, but no major advances in the fight against HIV. There was also little increased understanding about the causes or treatment of metabolic complications and body-shape changes observed in people on antiretroviral therapy (see Lipodystrophy conference coverage in this issue). There was, however, an encouraging plenary session on vaccines, presented by Dr. Gary Nabel, director of the National Institutes of Health (NIH) AIDS Vaccine Development Program. He noted that there are 70 early Phase I trials, 5 Phase II trials, and 2 large Phase III trials of vaccines currently ongoing. Hope also came from the data on Abbott Labs' new protease inhibitor Kaletra®, which was approved for marketing by the FDA two days before the meeting (see New Anti-HIV medications, below).
At the opening session, Martin Hirsch, M.D., a researcher from Harvard Medical School, took a reflective look back at the first 20 years of the AIDS pandemic. He divided the past two decades into developmental stages:
1986-90 "Birth" -- use of zidovudine monotherapy, beginning of cooperative trials groups such as the ACTG, and initial studies of dual nucleoside analog therapy.
The Combine study is a randomized, open label, multicenter trial comparing nelfinavir (Viracept®, a protease inhibitor) to nevirapine (Viramune®, a non-nucleoside RTI) in HIV-positive, treatment-naive people. A total of 142 participants were randomized to one of two regimens: Combivir® (ZDV 300mg/3TC 150mg, twice a day) with either nelfinavir (1250mg twice a day) or nevirapine (200mg twice a day). Statistical analysis showed that the ability of each combination to raise a person's CD4 count was equal (an increase of more than 130 CD4 cells was observed in both groups), but that people taking nevirapine were more likely to have undetectable viral loads. [In an intent-to-treat analysis at 36 weeks, 55.7% (nelfinavir) and 70.8% (nevirapine) had HIV RNA viral load less than 200, while in an on-treated analysis 78% vs. 83% had HIV RNA viral load less than 200, respectively. At 36 weeks, 38.6% (nelfinavir) vs. 66% (nevirapine) had HIV RNA viral load less than 20 by ITT analysis.
There had previously been some concern that it was not safe to use NNRTIs to treat individuals with high viral loads, but nevirapine worked well for this group, too. At entry, 33% of all the participants had HIV RNA viral loads over 100,000 and 20% had CD4 cell counts below 200. Even in people with baseline HIV RNA viral loads greater than 100,000, a higher proportion of the nevirapine group had undetectable HIV RNA viral loads (less than 200 copies/ml) by intent-to-treat analysis (85% vs. 61.5%). About 20% of people switched initial therapy due to adverse effects. Additionally, this study had a high discontinuation rate of 39%. While this is a relatively small trial, with a high discontinuation rate, it is another trial which shows that a non-protease inhibitor combination regimen may be as effective as, or even better, than a protease inhibitor-containing three-drug regimen at suppressing HIV RNA viral load over the course of almost one year follow up.
Glaxo Wellcome Inc., the makers of the anti-HIV medication Ziagen® (abacavir), recently sent a letter (August 2000) alerting healthcare providers to a previously unrecognized risk for people stopping and starting therapy while taking Ziagen®. There have now been seven cases of hypersensitivity reactions (HSR) to Ziagen® in people who stopped and restarted therapy after having been on Ziagen® for an extended period of time.
Initially, the biggest concern about Ziagen® use was that a few people who stopped Ziagen® therapy because of an early HSR (within the first few months) died as a result of restarting therapy. The latest letter to healthcare providers now indicates that illness and death are still a risk for some people who stop and restart Ziagen® therapy, even if they did not initially have obvious symptoms of a HSR.
Common symptoms of the Ziagen® HSR include fever, rash, nausea, gastrointestinal symptoms (nausea, vomiting, diarrhea or abdominal pain), and fatigue or malaise. Approximately 20% of people experiencing HSR also have respiratory symptoms such as cough, dyspnea (shortness of breath), and pharyngitis (sore throat).
According to the letter from Glaxo Wellcome, the majority of the people experiencing ill effects after restarting Ziagen® therapy actually did have mild, undiagnosed cases of hypersensitivity when beginning Ziagen®. While this delayed hypersensitivity reaction does not appear to be a common occurrence, a few points should be emphasized:
The recommendations for people restarting Ziagen® are as follows:
With the appropriate precautions noted above, based on what has been reported to date, it does appear that it is reasonable to restart Ziagen® if it is a drug that is an important component of your antiretroviral regimen. What is less certain is whether people who are taking Ziagen® should participate in trials of drug interruptions, when they may have multiple, possibly dangerous, re-exposures to Ziagen®.
A retrospective analysis of one study looking at people who had interrupted therapy while taking Ziagen® was presented by Melanie Thompson, from Atlanta, at ICAAC. In this review of 161 people on Ziagen®, adherence was monitored by computerized pill bottle caps. These bottle caps, called MEMS caps, measure the number of times a medicine bottle is opened. Seventy-four percent of the 161 people had interruptions of longer than two days. However, no HSRs were seen after treatment interruptions, and overall the rate was only 2.5%. This data suggests that while care should be exercised when Ziagen® is restarted after a treatment interruption, the risk of HSR with repeated interruptions does not appear to be increased.
The most newsworthy new anti-HIV medication is the latest protease inhibitor (PI) Kaletra (formerly ABT-378, also known as lopinavir/ritonavir). Kaletra capsules contain a new protease inhibitor, lopinavir, along with a small amount of ritonavir, allowing for high blood levels of the drug. The FDA's approval of Kaletra was announced just prior to the conference, and prescriptions are now being filled. Promising results were presented for both antiretroviral-naive and drug-experienced people. A Phase II study of drug-naive people on the now-approved dose of Kaletra showed that 96% (47/49) of people on treatment at the end of 96 weeks had viral loads below 400 copies/ml. A subset of people began on a slightly lower dose of lopinavir/ritonavir, and switched to the now-approved dose at week 48: 93% (27/29) of these people still in the study at week 96 had viral loads less than 400 copies/ml. The most common side effects observed were diarrhea and nausea, but only two of the original 100 subjects discontinued because of adverse events.
A Phase III study of drug-naive people compared the same combination, (Kaletra, Epivir [3TC, lamivudine] and Zerit [d4T, stavudine]), to Viracept (nelfinavir) taken three times a day with the same two NRTIs. Data for this study was on a total of 653 subjects. At 40 weeks of follow up, 79% of people taking Kaletra, compared to only 64% of those on Viracept, had viral loads below 400. In addition to the data on the effectiveness of Kaletra in a "real-life" combination, this Phase III study also provided an opportunity to look at what factors contribute to the failure of a regimen containing this PI. In 18 blood samples analyzed from people who had virologic failures while on Kaletra, not a single PI mutations was found. It has been difficult for researchers and clinicians to understand what these results mean for subsequent treatment options, but it appears that resistance to the lopinavir/ritonavir combination is relatively difficult to develop.
More data was presented on a protease inhibitor (PI) called BMS-232632 in development at Bristol-Myers Squibb in a slide session titled, "Safety and Antiviral Efficacy of Once-Daily HIV-1 Protease Inhibitor BMS-232632: 24 Week Results from a Phase II Clinical Trial." BMS has shown potent activity against HIV and a favorable resistance profile in the test tube. Phase I studies have also shown good safety and tolerability of a once-daily dose in people. This Phase II multinational, randomized study compared the safety and antiviral activity of three dose-levels of BMS with nelfinavir (Viracept®, NFV) in 750mg doses taken three times a day in a total of 92 treatment-naive people with HIV RNA viral loads greater than 2,000 copies/ml. Each PI was given as monotherapy for two weeks, and then in combination with ddI (Videx®) and d4T (Zerit®). The three levels of BMS studied were 200, 400, and 500mg, all once a day. BMS was well tolerated both alone and in combination.
The most common adverse events were diarrhea (29% BMS, 75% NFV), and nausea (24% BMS, 15% NFV). There were no elevations in cholesterol or triglycerides observed. Elevated levels of bile in the blood (unconjugated hyperbiliru-binemia) were observed, but were not associated with any other liver abnormalities. (This abnormality is not clinically significant, and is similar to that seen with indinavir [Crixivan®]). With two weeks of monotherapy, people on both BMS and NFV had reductions in viral RNA levels of about 1.5 log. Virologic results at 24 weeks of follow-up showed that 65% of those on the 500mg dose of BMS had viral loads below 400 (as compared to 67% of people taking NFV) and 35% had viral loads below 50 (as compared to 38% of people taking NFV). These are encouraging results for a once-a-day PI. Studies are ongoing to determine if this new PI will be active against HIV that has developed resistance to other PIs.
Early study data on the investigational protease inhibitor DMP-450 from Triangle Pharmaceuticals showed promise. A Phase I/II study of 15 individuals compared several doses and dose schedules of the new compound to Crixivan (Indinavir) taken every eight hours. Both PIs were used in combination with Zerit (stavudine, d4T) and Epivir (lamivudine, 3TC). There was earlier concern about this compound's effect on the heart, but this study showed no cardiac abnormalities. Comparable and significant reductions in viral load were seen in each subgroup of the study, suggesting that the compound is safe, effective and warrants further research.
More data was presented at ICAAC suggesting a unique resistance profile for tipranavir, a PI slated for approval in 2003. This compound has seen delays in its development due to its recent transfer from one company to another. Another problem in tipranavir's development is the fact that a small amount of ritonavir will need to be included to keep drug levels high enough to allow for twice-a-day dosing. The resistance pattern of this drug in the test tube, however, is very promising. The data presented at ICAAC suggests that tipranavir is effective against HIV viruses which contain up to eight protease inhibitor resistance mutations.
Investigation into DAPD, a NRTI from Triangle Pharmaceuticals, has progressed from the test tube to the first early studies in HIV-positive people. Results of this research, looking at the safety, effectiveness and resistance profile of the compound alone and in combination, seem to indicate that DAPD is able to inhibit virus that is resistant to Retrovir (AZT, zidovudine), Epivir (3TC, lamivudine), or Ziagen (abacavir) and works well in combination with other anti-HIV medications.
Results were presented from a Phase II study of the addition of the nucleotide analogue tenofovir to the regimens of 189 HIV-positive individuals with detectable viral loads. The compound appears to have good activity against viruses resistant to other anti-HIV medications, and was well tolerated by all study participants. Tenofovir is chemically similar to the failed nucleotide analogue adefovir, but does not seem to have the negative effect on the kidney that prevented the approval of adefovir as an anti-HIV medication earlier this year.
Several presentations and posters at ICAAC highlighted a new category of anti-HIV drugs called entry inhibitors. Entry inhibitors work at a variety of new target sites, preventing virus particles from connecting to and entering host cells. The steps for which inhibitors are being developed are attachment, coreceptor binding, and fusion. None of the entry inhibitors, except the fusion inhibitor T-20, have been looked at in humans. Data presented at ICAAC focused on the promising synergistic effects, seen in the test tube, of combinations of entry inhibitors.
Another new class of compounds being looked at are inhibitors of the integrase enzyme. Integrase is responsible for irreversibly combining HIV's genetic material with the host cell's DNA. Although no compounds have yet been tested in humans, researchers are planning ahead by looking for mutations which will lead to reduced susceptibility to individual compounds, cause cross-resistance among integrase inhibitors and/or between drug classes.
The steroid prednisone is often used to suppress allergic reactions, so it is reasonable to wonder if it could be used to prevent the skin rash that is often seen when people begin the NNRTI nevirapine. This rash occurs in about 15% of people. Researchers in Spain conducted a randomized, double-blind, placebo-controlled trial comparing placebo to prednisone (30mg/day for 2 weeks) in people starting on nevirapine-containing regimens. Surprisingly, the incidence of rash so severe that it caused discontinuation of the medication was higher in the prednisone-treated group (13%, versus 3% in the placebo group). This study is a good example of the need for placebo-controlled, double-blinded studies to address questions like this (Abstract L-15). A different poster reviewed earlier non-randomized studies evaluating the use of different treatments to decrease the incidence of rash from nevirapine. Overall, rate of rash in people who did not take any anti-inflammatory medication ranged from 14 to 19%. In people taking prednisone (or closely-related prednisolone), incidences of rash ranged from 1 to 36% in different studies. When people were given antihistamines, the rates ranged from 5.8 to 8.2%. In people who started with a lower dose of nevirapine and gradually increased to full dose, the incidence was 11.2%. The incidence of rash when combining this slow dose escalation with prednisolone was 7.8%.
The potential virologic and immunologic benefits of adding Il-2 to HAART were investigated in a study called CPCRA 059 presented by Donald Abrams. Il-2, short for interleukin 2, is an immune stimulant that is given as an injection under the skin. One of the major problems with Il-2 is that most people get a flu-like syndrome after each injection. The study randomized 511 people who were on HAART to receive either no Il-2, 4.5 MU of Il-2 or 7.5 MU of Il-2. The Il-2 was given twice a day for 5 days, every 8 weeks. This cycle was repeated three times and then as needed to maintain CD4 cell counts at twice the baseline number, or over 1,000. The results showed that after 12 months there was no difference in the control of HIV RNA viral load between the three groups. This large study, like others, shows that while Il-2 does raise CD4 (T helper) cells, it does not appear to affect the control of HIV by HAART. There is currently a large international trial, ESPRIT, which will attempt to follow a large number of people long enough to answer the most relevant question concerning Il-2: Is there a difference in clinical outcomes when Il-2 is added to HAART?
The newly developed strategy of using interruptions in therapy (known as "structured therapy interruptions," or STI) to stimulate HIV-specific immune responses has shown promise when used in people who began HAART immediately after becoming infected with HIV. By beginning HAART during primary infection, the immune system's HIV-specific responses are not destroyed by very high levels of the virus. Researchers are currently investigating the idea that a person who has preserved these natural HIV-specific responses may later go off HAART therapy (with an undetectable viral load), and his or her immune system may be able to maintain control of the virus without antiretroviral medications.
Eric Rosenberg, Bruce Walker, and colleagues from Harvard Medical School published a very significant paper in the journal Nature on September 28, 2000. They reported the results of treatment interruptions in people treated with HAART within 72 hours of being diagnosed in primary HIV infection. It is very important to note that the promising results reported in this study were not seen when STI was used in people who began HAART after they had been infected with HIV for any length of time. Sixteen people were treated with HAART within 72 hours, before HIV antibodies were detectable. The diagnosis was made by checking HIV RNA viral loads in people who presented with symptoms of primary HIV infection and a history of recent, possible exposure to HIV. Symptoms include a severe flu-like syndrome, with fever, sore throat, swollen lymph nodes, and a rash and are sometimes known as "sero-conversion flu."
Immediate treatment with HAART was shown to preserve strong immunologic responses to HIV. The researchers evaluated eight people who had good virologic suppression on their initial HAART regimen (HIV RNA viral load less than 50 for more than eight months) then had several four-week interruptions in HAART. After each treatment interruption, there was a slower rebound in HIV RNA viral load, as well as improved immunologic responses to HIV. Currently, five of the eight people remain off HAART, with good immunologic control of HIV levels (HIV RNA viral load <500 copies/ml). These five have been infected for an average of 2.7 years.
The authors emphasized that enhanced immunologic responses to HIV are not seen when treatment interruptions are used in people started on HAART who have chronic HIV infection, (i.e., when HAART is not started at the time of primary HIV infection). Only about 70% of people, however, have symptoms of primary HIV infection when they are first infected with HIV. Those that do are often misdiagnosed as having the flu. However, primary care, urgent care, and emergency room providers need to be alert to this syndrome. Unless an HIV RNA viral load is checked, the diagnosis cannot be made. In the past it was less critical (in terms of future therapy options), to make a diagnosis at the time of primary HIV infection. However, if the above data is verified (by studying more people for longer periods of time), it may be very important to make the diagnosis of primary HIV infection in order to take advantage of this strategy. Both the general public and healthcare providers need to think carefully when someone has the symptoms described above. Providers need to take a careful history and order an HIV RNA viral load test if primary HIV infection is suspected.
At ICAAC, researcher Franco Lori presented some very provocative data using treatment interruptions after treatment of primary simian immunodeficiency virus (SIV) infection in macaques. After four treatment interruption cycles of 3 weeks on therapy, 3 weeks off therapy, none of the six animals treated during acute infection had viral rebound, compared to all four of the animals that were chronically infected when they began treatment. Franco Lori stated that he tried to model in the macaques what had occurred in the "Berlin Patient," a person treated at the time of primary HIV infection, who now maintains an undetectable HIV RNA viral load without medication, following several treatment interruptions.
At the opening press conference of the ICAAC, Dr. Michael Saag, a prominent HIV researcher, was asked if the standard of care should be to treat all people who are diagnosed during primary infection. Dr. Saag joked that data from eight people and a few monkeys might be a little shaky to establish a standard of care. He did note, however, that there is increasing evidence that there may be a window of opportunity to preserve strong HIV-specific immune responses. This opportunity exists if someone begins treatment during primary HIV infection, but appears to be lost if treatment is delayed.
Several presentations illustrated data showing successful discontinuation of preventative therapy for opportunistic infections (OIs) in the HAART era. Of special interest were findings that showed that prevention (or prophylaxis) may be stopped, when the immune system is restored, even if a person has a history of active infection. Preventative medication in the case of previous active infection is known as "secondary prophylaxis."
Toxoplasmosis, caused by a protozoa, is a relatively common infection in immunosuppressed people. It causes growths in the brain and is life-threatening. For people who have had an active infection and stop treatment, the recurrence rate is up to 20% per year if the immune system is not reconstituted. However, a study presented at ICAAC reported on the outcome of a randomized study of stopping toxoplasmosis preventative therapy in people on HAART who had T helper (CD4) cell counts above 200 for more than three months and an HIV RNA viral load less than 5,000 copies/ml. All of the 438 people in the study had antibodies to toxoplasmosis, indicating prior exposure to the protozoa, and 54 had a history of active infection. After a median follow-up of 21 months in the primary prophylaxis group (people with antibodies, but no prior clinical disease), and 12 months in the secondary prophylaxis group, there were zero episodes of clinical toxoplasmosis. This study suggests that it is safe to stop toxoplasmosis preventative therapy in people on HAART who have T helper cell counts above 200 for more than three months, and good virologic suppression. (ICAAC Abstract L-16).
A group from Italy presented a small observational study in which 14 out of 24 people with a history of cryptococcal meningitis (crypto) discontinued prophylaxis for crypto after regaining an average CD4 cell count of 251 (six of the people stopped prophylaxis with CD4 counts less than 100). After 27 months of observation none of the 24 people had a new episode of cryptococcal meningitis. This study is not adequate to change current guidelines, but does contribute to a growing consensus that it may be safe to stop secondary prophylaxis for cryptococcal meningitis.
A Spanish study of discontinuation of secondary prophylaxis for cytomegalovirus (CMV) retinitis also showed low rates of recurrence of disease. This study looked at 36 people who had viral loads less than 500 copies/ml and CD4 counts greater than 100 and who had not had active CMV-retinitis for three months before discontinuing prophylaxis. After a median follow-up time of 90 weeks, only one person had a relapse of CMV. However, this person's CD4 count had dropped to only 62 and his or her viral load had increased to 715 at week 40.
These studies mirror data presented at last year's ICAAC that supported the discontinuation of primary and secondary prophylaxis for mycobacterium avium complex (MAC) and pneumocystis carinii pneumonia (PCP) when CD4 cells rise above 200.