The Ultimate Battle Must Be Won By The Immune System
Over 12,200 health care providers and medical researchers from 90 countries came together in San Francisco for one of the largest infectious disease conferences in the world, the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), from September 26 to 29, 1999.
The meeting might be summed up as one clinician put it: the immune system needs to be thought of as a drug that's always available and for which there is no worry about adherence. (If we could just figure out a way for pharmaceutical companies to make money off of the immune system, real investment and progress might be seen!)
One of the highlights of ICAAC was a debate about "hit hard, hit early" versus "hit hard, but hit later." Because leaders in the field are acknowledging that eradication of HIV with current treatment regimens is not possible, the timing of initiation of HAART is now a debate. However, with that reality, which became apparent in the last 18 months, there is now a serious focus on immune-based approaches to control HIV. Based on the evidence that 5% to 10% of HIV-infected people appear to be able to control HIV replication long-term, and considering the failure of eradication, major research is being conducted on methods to boost the immune system, and specifically its control of HIV replication. Coincident with this renewed focus have been significant advances in laboratory methods to measure HIV-specific immune responses.
The opening session at ICAAC featured presentations by Anthony Fauci of the National Institute of Health (NIH), John Mellors from the University of Pittsburgh, and Joep Lange from the Netherlands. According to Dr. Fauci, who directs the HIV research program at the NIH, the two most important tasks are stopping opportunistic infections (which stimulate HIV replication) and finding and ridding the body of the reservoirs of cells latently-infected with HIV (which are the source of HIV replication as soon as antiretroviral therapy is stopped in almost all people).
In contrast to the World AIDS Conference in 1996, when there was hope (and hype) of eradicating the virus from the body, the reality is that HIV persists even after long-term suppression by three- and four-drug combinations. Dr. Fauci reviewed his lab's pivotal work, and that of others that identified reservoirs of resting CD4 cells that are infected with HIV, the so-called "latent pool." The hidden virus lies "sleeping" in CD4 cells in the lymph nodes, and possibly other organs, and is not eliminated by today's antiretroviral regimens. Even when HIV is detected right after initial (or primary) infection and treated with HAART immediately, pools of latent cells are already established. It is from these reservoirs that, regardless of the effectiveness of HAART, viral replication occurs rapidly when HAART is stopped.
Dr. Fauci outlined three basic approaches to control HIV:
One of several immune-based therapies currently under investigation is general immune stimulation, or enhancement of HIV-specific immunity. The goal of immune-based therapy is to eliminate the latent pool or keep it contained so there is no ongoing HIV replication and resultant loss of CD4 cells. According to Dr. Fauci, interleuken 2 (IL2) is one of the best options under investigation. A recent NIH study examined 14 people on HAART plus IL2, and compared them to 12 people on HAART alone. Overall, the people on IL2 had lower viral loads and 3 of them actually had no trace of HIV in the lymph nodes. But, once therapy was stopped, all 12 had HIV viral rebound. HAART may stop HIV replication, but it does not completely eliminate HIV infected cells from the body.
What exactly is treatment failure? According to Dr. John Mellors, it is when a drug regimen fails to suppress HIV replication to below 50 copies/ml in the blood. The causes of treatment failure include inadequate regimen potency; too low a blood level of the drugs; lack of adherence to a prescribed regimen; resistance, which may be pre-existing, transmitted, or selected; and advanced disease, measured by very low CD4 counts or a very high viral load. Regardless of how failure is defined, it has severe consequences: viral escape, decline in CD4 cells, and clinical progression. How fast progression occurs is dependent on several factors, including viral load (HIV RNA) and rate of increase; CD4 count; residual HIV-specific immunity; and viral fitness (the ability of the resistant virus to infect and kill CD4 cells).
Treatment failure limits future treatment options. When resistance occurs to one drug in a class, it usually results in resistance to all currently available drugs in that class (known as cross-resistance). Even when a primary mutation does not confer cross-resistance, it seems to prime the virus to develop resistance to the other drugs in the same class, as is seen with some protease inhibitors (PIs). Treatment failure is not uncommon. Dr. Mellors cited the data from the Swiss Cohort Study, which showed that in drug-naïve people using a PI-containing regimen, at least 10% fail within the first year, and 20% fail by the second year. For people with prior antiretroviral treatment experience, 20 to 30% experience drug failure within one year, and 30 to 40% fail within two years. Recent unpublished data from the HIV Cost and Services Utilization Study, a national survey cited by Dr. Mellors, found that one-third of all people currently on HAART have viral loads over 20,000.
When to switch therapy and what to switch to are the questions that healthcare providers and people with HIV are struggling with and about which there is little data. An increase in viral load of more than 1,000 is a strong indication to switch. Dr. Mellors recommended the following steps when considering switching to salvage therapy:
Dr. Mellors reviewed some potentially beneficial drugs in development. Adefovir is a new nucleotide reverse transcriptase inhibitor (NRTI) that may be beneficial when used with other new drugs. But adefovir is not active against AZT-resistant HIV, and causes reversible kidney damage in 50% of people at the 120-mg dose. However, a study was presented at ICAAC by Gilead that showed that after 24 weeks, a 60-mg dose of adefovir resulted in the same viral suppression as the 120-mg dose, but without kidney damage. But it remains to be seen if kidney damage occurs with longer therapy at the 60-mg dose. (Other new drugs discussed later in this review include tenofovir, ABT-378, and T-20.)
The last speaker of the opening session, Dr. Joep Lange presented his studies of five-drug regimens that can suppress the viral load to below 5 copies/ml. However, even at that level, some cells in the blood that are capable of producing HIV could still be isolated. His group is using antibodies directed at the latently-infected cells in an attempt to destroy them. He was skeptical about strategic therapeutic interruptions (drug holidays), which he likened to "drinking whiskey to avoid alcoholism." Dr. Lange noted that although stopping and restarting HAART has been done repeatedly and the viral load has always rapidly increased, only the few positive anecdotes seem to survive.
Some of the trails Presented at ICAAC were examining new drugs in early stages of development, while others presented follow up data to ongoing studies of currently available drugs.
Sustiva spares a PI
The most celebrated study presented at the last few major conferences has been DuPont's 006 study, which compared three unique combinations in an open label study. The study has three arms, AZT+3TC+ Crixivan, AZT+3TC+ Sustiva and Crixivan + Sustiva. Dr. Staszewski presented the results of each of the arms after participants had been on therapy for 72 weeks, looking at both efficacy and tolerability.
In a group of 450 people who had been on treatment for 72 weeks, the researchers found the Sustiva containing triple combination performed better than the Crixivan containing triple combination. In an analysis that counted study drop-outs as treatment failures, (intent to treat), 60% on Sustiva compared with 40% on Crixivan had viral loads below 50 copies/mL. In an analysis of only those still on therapy, (as treated), 89% on Sustiva, compared with 81% on Crixivan, had viral loads below 50 copies/mL. This study suggests that a triple combination therapy including Sustiva should be considered as a viable option for initial therapy.
Study shows Ziagen and Crixivan have equal power, but Crixivan works better for people with higher viral load.
Earlier data had been presented comparing a triple nucleoside reverse transriptase inhibitor (NRTI) combination to triple combination including a protease inhibitor (PI). Dr. Staszewski presented the results at 48 weeks of a study that compared AZT+3TC+ Ziagen to AZT+ 3TC + Crixivan. This study was somewhat unique because it required all study participants to take 16 pills a day, follow difficult food restrictions, and every eight hour dosing schedule necessary with a combination including Crixivan. The study included 562 drug naïve people with a mean viral load of 63,000 copies and a CD4 count of 360 cells. Both groups experienced a very high drop-out rate with 55% of the people on the Ziagen arm reaching 48 weeks, compared to only 45% on Crixivan.
In an intent to treat analysis, 51% of the people on both of the combinations had viral loads below 400 copies/mL. In the as-treated analysis, 86% of the people on the Ziagen arm, and 94% on the Crixivan arm had viral loads below 400 copies/mL. The results of the analysis suggest that the two combinations are comparable, but there seems to be a difference in response when analyzing the same people with a viral load assay which can detect down to 50 copies/mL. With the more sensitive test, 46% of the people on Crixivan and 40% of the people on Ziagen were below 50 copies at 48 weeks. Data was also presented which suggested that people who started with viral loads over 100,000 copies/mL responded better in the Crixivan arm. Of the people with over 100,000 copies/mL, 46% on Crixivan, and only 31% on Ziagen, had viral loads below 50 copies/mL at week 48 of the study. It is important to note that adherence to the difficult dosing schedule required by the study might have had some impact on the outcome.
Data shows good results for twice-a-day dosing
Dr. Calvin Cohen presented a study which compared Fortavase in combination with 2 NRTI's taken twice a day versus three times a day and Fortavase and Viracept in combination with one NRTI. The study consisted mainly of antiretroviral naïve participants (75%) but did allow for people who had previously received antiretrovirals. There were 838 people in the study, with a mean viral load of about 50,000 copies/mL and a CD4 count of 310 cells.
All three arms of the study performed equally well, with between 58% to 60% of the people below 400 copies/mL, in an intent to treat analysis, and 80% of the people in each arm below 400 copies/mL in an as-treated analysis. When viral load was tested to below 50 copies again the results overlapped with 40% below 50 copies/mL, on an intent to treat analysis, and that number rising to 60% on an on-treatment analysis. The number of CD4 cell increases in the study were also overlapping ranging from 140 to 150 cells.
This data is good news to anyone currently taking Fortavase three times a day, and it also suggest that the twice a day dosing requirement performs just as well.
Some healthcare providers have been reluctant to use PI-sparing regimens due to the lack of data about NNRTI regimens and changes in lymph nodes. An NIH study compared 9 people on a three-drug regimen of d4T, 3TC, and efavirenz (Sustiva) to 4 people on a three-drug regimen of a PI and two NRTIs. There was comparable improvement in lymph node structure in both groups when the viral load was suppressed to less that 50 copies/ml. This is the first study to report on the comparison of lymph node architecture with these two treatment approaches. In both the efavirenz and PI groups there appeared to be development of some low-level resistance to the NNRTIs delavirdine and nevirapine, even though those drugs were not administered to any of the people in the study. No people in the efavirenz group had any evidence of resistance to efavirenz in the virus isolated from their lymph nodes. This small study should make people more comfortable with NNRTI, or PI-sparing, regimens.
HIV Rebounds after successful HAART is Stopped
Dr. Marty Markowitz of the Aaron Diamond AIDS Research Center presented a study titled "Virologic and Immunologic Profiles of Newly Infected Individuals Electing Discontinuation of HAART after Approximately Three Years of Apparently Suppressive Therapy." In this study, four people, who began treatment with HAART (ZDV, 3TC, and one PI) between 7 and 90 days after the onset of symptoms of primary HIV infection, elected to discontinue treatment after 931 to 1,191 days of apparently completely suppressive antiretroviral therapy. Subsequently, subjects were seen weekly for 4 weeks then every 2 weeks for virologic and immunologic studies. The four people were self-selected and their HIV rapidly rebounded after stopping HAART. Within 24 days they had viral loads up to10,000 copies/ml and their CD4 cells decreased, but one of the four had a drop in viral load to near non-detectable after an initial increase. There was variable evidence of development of HIV-specific immune responses after stopping therapy.
This study confirms many other reports that virtually all people experience rapid increases in HIV replication when HAART is stopped, even after long-term suppression. Dr. Markowitz observed that viral rebound appeared later in this group than in individuals who stopped HAART but had been infected longer before they started HAART. More study is needed to determine if stopping HAART after therapy for primary HIV infection results in a slower rate of disease progression.
Dr. Michael Saag of the University of Alabama presented results from a retrospective study of the use of phenotype resistance testing in people who had prior antiretroviral therapy. Most of the people had previously used PIs, but only 10% had received prior NNRTI therapy. When one looked at the results of the phenotype test, the number of new drugs selected, and prior PI use, the only result that was significant for predicting how well the new treatment regimen would work (as defined by time to failure on the new regimen) was the result of the phenotype test. While this was a retrospective study, and the results of the phenotype test were not used to select the new regimen, people who did the best were those who received the most drugs that the phenotype test showed they were not already resistant to. The major problems associated with the phenotype test are that the results take several weeks to obtain and it costs $800, with very few insurers willing to pay for it.
Trimeris, Inc. presented encouraging data about T-20, a fusion inhibitor which blocks the ability of HIV to get through the wall of a cell. In this study, 71 people received T-20 in addition to their other anti-HIV drug regimen. These people had a great deal of prior therapy and HIV drug resistance. After 16 weeks, 60% of people still on the trial had a viral load of less than 400 copies/ml. There was no control group for comparison, but this is much better than would be expected in such a group of heavily pre-treated people. This "proof of concept" trial showed that a new class of anti-HIV drugs, a fusion inhibitor, has a potentially significant clinical usefulness. Further trials need to compare groups with and without T-20, and longer follow-up is needed. Trimeris also has a second, possibly more potent, fusion inhibitor in development, T-1249. A major concern is that these compounds are small proteins and cannot be taken by mouth, so they are injected under the skin (subcutaneously) twice a day. The people in this trial were able to do this without much difficulty or adverse side effects.
Tenofovir Disoproxil Fumerate (TDV), a.k.a PMPA, Shows Promise
Dr. Robert Schooley presented some promising results on a once-daily NRTI, tenofovir, which is related to adenovirus. People with viral loads of 400 to 100,000 copies/ml on stable antiretroviral therapy with four drugs for 8 weeks prior to entry were randomized to receive 75, 150, or 300 mg of TDF or placebo at 22 United States sites. The 300 mg dose resulted in the biggest decrease in viral load (HIV RNA), a drop of 0.83 log after 24 weeks, compared to an increase of 0.28 log in the placebo group. Tenofovir had very little toxicity, and it is possible that even higher doses may result in greater viral suppression. Of concern is that tenofovir may cause kidney damage, as adefovir does in a significant number of people, but at least at 24 weeks, this was not observed in this study.
Abbott's New PI hits the streets
Abbott's new Protease Inhibitor, ABT-378 will be made available through expanded access starting in October, 1999 and is showing good results to date. ABT-378 is combined with a small concentration of ritonavir, and maintains very high concentrations in the blood. Dr. Joseph Eron reported results of treatment with ABT-378 after 36 weeks, in both people without prior therapy and people who had failed one prior PI. In the treatment-naïve group (no prior HAART), almost 90% of people had viral suppression to below 50 copies/ml when ABT-378 was combined with two NRTIs. In the group who had failed a prior PI, almost 80% had viral loadsuppression to below 50 copies/ml after 36 weeks.
However, the group of people who had failed one PI had not received prior NNRTI therapy, and in this trial ABT-378 was administered with an NNRTI, nevirapine, plus two new NRTIs. Still unknown is how well ABT-378 will work in people who have failed both PIs and NNRTIs. Also of concern were the significant elevations in triglycerides and cholesterol measured in these studies.
Probably the most exciting aspect of ABT-378 is that at the lowest blood level before the next dose, the trough, the drug concentration is still 30 times above the level needed to inhibit HIV replication. This means it has the potential to become a once-a-day drug.
ABT-378 is being made available through a compassionate use program on a limited basis and will become more available in January 2000. Company experts say that they hope to have ABT-378 FDA approved by October of 2000. Anyone can call 888-711-7193 for more information about eligibility (CD4 count below 50, or an active opportunistic infection while on a current regimen.)
Dr. Judith Currier presented the results of the ACTG 362 trial, which evaluated the safety of stopping azithromycin prophylaxis for MAC (mycobacterium avium complex) in people who had an increase in CD4 cells from below 50 to over 100 while on HAART. Of 643 people, half took 1,200 mg of azithromycin once a week and half took a placebo. After 56 weeks of follow-up, on average there were no significant differences in the rate of MAC infection in the two groups. (Recently, a CPCRA study observed the same findings.) Thus, it appears to be safe to stop taking prophylactic (preventative) therapy for MAC if your CD4 cell counts remain above 100 while on HAART.
Dr. Rob Murphy presented 48-week data on the Atlantic Study, a randomized, open-label trial comparing two PI-sparing antiretroviral strategies to a standard PI-containing regimen. In this study, 298 treatment-naïve people were randomized to one of three regimens: d4T and ddI and 3TC, d4T and ddI and nevirapine (NVP), or d4T and ddI and indinavir (IDV). Standard daily dosages of d4T, 3TC, and IDV were used, with ddI (at 400 mg) and NVP (at 400 mg) being dosed once a day. The preliminary analysis showed these results:
The results were not significantly different among the three treatment arms. However, people with higher viral loads (above about 12,000) were less likely to reach viral loads below 50 copies/ml in the triple-NRTI arm as compared to the other arms. The regimens were similarly well tolerated. These results, like those of the AZT, 3TC, and Abacavir study (discussed elsewhere in this review) raise serious concerns about the use of triple-NRTI regimens in people with high viral loads. Also of concern is the combination of ddI and indinavir because neither can be taken with food, nor can they be taken at the same time.
There were several reports at this year's ICAAC about less frequent dosing of already approved drugs, including the daily administration of ddI, ritonavir and indinavir, and ritonavir and saquinavir.
Dr. Joe Gathe reported on a trial titled "Comparison of a Triple Regimen Containing Once-Daily Didanosine vs a Regimen of ZDV/3TC/NLF." This study confirmed the findings of some earlier trials of administering ddI once a day. The combination of ddI (once a day), d4T (twice a day), and nelfinavir (three times a day) was compared to ZDV, 3TC, and nelfinavir in people with CD4 cell counts above 100 and viral loads above 2,000. The ddI was administered once a day in two 200-mg tablets. Once-daily dosing of ddI in a typical triple-drug regimen produced antiviral and immunological activity similar to the triple-drug regimen after 24 weeks of follow-up.
The use of once-daily ddI would be helpful to many people because ddI must be taken on an empty stomach, and some of the side effects may be related to the buffer (a compound to reduce stomach acid) contained in the ddI tablets. Bristol-Myers Squibb is working on a newer formulation of ddI and hopes to have an enteric-coated tablet available sometime next year that need not be taken on an empty stomach.
Dr. Michael Saag presented a poster titled "Saquinavir Systemic Exposure and Safety of Once Daily Administration of FortovaseT (Saquinavir) Soft Gel Capsule (FTV) in Combination with Low-Dose Ritonavir (RTV)." The 41 HIV-negative volunteers completed an open-label, randomized, parallel group study of either fortovase (FTV) alone three times a day (arm A) or FTV in various combinations with ritonavir (RTV) once a day (arms B through E). Volunteers received one of the regimens following standard dinners (900 calories, 35% fat) for 13 days. All regimens were well tolerated.
IDV/RTV (mg): 800/200; 800/100; 1,200/100; IDV placebo/100; or IDV placebo/200.
Levels of drug in the blood were tested on day 14 over a 24-hour period. All once-a-day regimens produced IDV levels comparable to standard therapy and were generally well tolerated. Dr. Saah concluded that once-daily dosing regimens of IDV with RTV should be evaluated for clinical efficacy. (The once-a-day regimens give an initially higher level of IDV, so it remains to be seen if there will be more problems with kidney stones, or other toxicities in larger, longer trials.)
Dr. Veronica Miller reviewed structured treatment interruptions (STIs), or the art formerly known as "drug holidays." STIs have been studied in three different situations: following treatment for primary HIV infection (where HAART is started within a short time after one acquires HIV infection); during interruptions in therapy when one has had long-term suppression of HIV in the chronic treatment situation; and lastly, as a treatment break when failing on a current regimen, with high viral load, before starting a new "salvage regimen." Dr. Miller emphasized four variables to consider in any of these situations: the immune system, the HIV, the antiretroviral drugs, and "being human." As many presenters noted, current treatment regimens do not eradicate HIV even after 3 or 4 years of excellent viral suppression, with viral loads consistently below 50 copies/ml. Can we expect people to take complex regimens for decades?
The virologic factors yet to be studied include rebound dynamics, response to subsequent therapy, viral evolution, development of resistance, and reseeding of the latent reservoir. Dr. Miller also reviewed her earlier study of the effect of a treatment interruption prior to starting on a new salvage regimen, when someone has poor virologic control on the current regimen. She observed that two-thirds of people had their HIV revert back to "wild type" or drug-sensitive type, indicated by resistance tests. In the group that had reversion to wild type, there was better and more prolonged suppression of HIV by the new treatment regimen. However, there were significant increases in viral load and major decreases in CD4 counts during the no therapy period.
Dr. Miller noted that one poster (Abstract 1828, "Restoration of Immunity after HIV Infection" by E.L. Jacobson of Cornell University) presented a study in which low-dose interleukin 2 (IL2) was continued during the treatment interruption period. In this study, three people remained off of HAART with very low viral loads.
Dr. Franco Lori and a Barcelona group have reported that when STIs are done several times there appears to be a slower rebound of the HIV on each subsequent stop, but no new data was presented at ICAAC on this topic. There are several studies ongoing, or being planned, to address STI issues. Dr. Miller concluded with this cautionary note about stopping therapy: "Mind the gap!"
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.