Chelsea & Westminster Hospital.
Medical Consultant
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IMMUNOLOGY & IMMUNOTHERAPEUTICS
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A brief interruption in highly active antiretroviral therapy (HAART) in HIV-infected patients who begin treatment during acute infection can generate HIV-specific immune responses that are not induced earlier, despite the presence of extremely high viral loads.
Dr. Bruce D. Walker at Massachusetts General Hospital in Boston told participants at the 12th Colloque des Cent Gardes meeting this week about his group's experience to date with such patients. Dr. Walker's group has been recruiting patients with acute HIV infection, which they define as individuals at the pre-seroconversion stage - ELISA negative but HIV RNA positive - who are then started on HAART. The patients' mean plasma viral load at diagnosis was 13.8 million RNA copies/mL. Only 3 of the 21 patients evaluated had detectable T helper cell responses at diagnosis. Dr. Walker's group also detected cytotoxic T lymphocyte (CTL) responses in 10 of the 15 evaluable patients, but unlike T helper cell response, CTL response did not increase over time after therapy began.
After 1 year on HAART, therapy was discontinued in a subset of seven patients, he explained. This led to a rebound in viraemia, but also to a boost in cellular immune response, which was the first detectable CTL response for some individuals. One patient underwent a second interruption in therapy, and another underwent HAART interruption three times. Dr. Walker's group observed a blunting of viral load and a broadly directed CTL response in these two patients. Both patients ultimately resumed HAART.
It appears that with the initiation of HAART, "...CTL response is put to rest," Dr. Walker told the audience. However, a brief interruption, resulting in a second exposure to virus, augments T helper response and CTL response. Dr. Walker stressed that this was a very select group of patients, who were diagnosed and treated during the very acute stages of HIV infection, not people who were chronically infected. Therefore, the findings would not apply, at this stage, to most patients. "Basically what we've been doing is trying to see if a brief therapeutic interruption will lead to augmentation of immune responses, and what we find is that it, in fact, does. Whether that translates into clinical benefit is not yet clear," he continued. "But the data suggest that you can actually manipulate the immune response in people who are HIV-infected." Their next step will be to try to induce helper cell responses in patients who are chronically infected, by using specific therapeutic vaccinations. To this end, they are currently using the Remune immunogen.
"I think the next big advances in treatment are going to come from a combination HAART and immunotherapy," Dr. Walker commented.
Ref: Eric Rosenberg, Markus Altfeld, Sam Poon, Robert Eldridge, Barbara Wilkes, Bruce D. Walker. Effects of treatment and treatment interruption on cellular immune responses in acute HIV infection. 12th Cent Gardes Symposium, October 25-27, 1999. Paris, France. Source: Reuters Health.
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Anti-HIV T-helper cell responses may be present in very early infection and preserved by rapid initiation of antiretroviral therapy. However, it would appear that the CD8 mediated anti-HIV CTL responses may not be fully developed prior to therapy, and indeed, may then wane with effective viral suppression. These data are supported by the abstract below (also presented at this meeting). It appears increasingly likely that anti-HIV CTL responses are crucial in determining "set point" and hence, ultimately, the rate of disease progression. They are also likely to be a key determinant of viral rebound during antiretroviral treatment as the CTL contribution declines with time on maximally suppressive therapy. What we need to know now are the important aspects of the CTL response. Can lost CTL responses be recovered? Is ongoing HIV-specific T helper cell response necessary? Which viral antigens stimulate the best CTL response? Which chemokines are needed? Can co-therapies (IL-2, Remune, other cytokines) help maintain CTL and if so does this change the off-therapy set point? The answers to these crucial questions should guide the design of therapy interruption studies. |
Abstract
Purpose of the work : To determine whether the development of anti-HIV CD8+ T cells in HIV-1 primary infection is subject to specific alterations.
Background : The cellular immune response appears to be the main effector involved in controlling viral replication during HIV-1 and SIV primary infection. However, the immune response fails to eliminate the virus from the host during acute infection which is then followed by chronic infection with persistent HIV replication. The reasons for this incomplete control of viral replication are not clearly understood.
Methods : We used IFN-g ELISPOT assay and intracellular staining to characterize the ex vivo anti-HIV CD8+ T cell responses in 24 subjects with early HIV primary infection. We evaluated the breadth of the CD8+ T cell repertoire induced by using a wide variety of optimum HLA class-I epitopic peptides derived from the sequences of the env, gag, pol and nef genes of HIV-1LAI as stimulator antigens. The anti-viral repertoire of each subject was defined by the multispecificity of the response (assessed as the number of epitopic peptides recognized) and its intensity (assessed as the frequency of IFN-g-secreting cells). The anti-HIV CD8+ T cell responses of seroconverters were then compared to those of 30 asymptomatic subjects with chronic HIV-1 infection. They were also compared to the recently described CD8+ T cell responses specific for EBV in individuals presenting acute infection by this virus.
Results : We observed HIV-specific responses in only 71% of seroconverters as compared to 100% of chronically-infected individuals. Furthermore, the number of peptides recognized per individual was significantly lower in patients with acute HIV-1 primary infection (median 2, range 0-6) than in the 30 asymptomatic subjects with chronic infection (median 5, range 1-13 ; P<0.0001). The frequency of HIV-specific IFN-g -secreting CD8+ T cells among PBMC for a given peptide was of the same order of magnitude in both groups and rarely exceeded 0,3%. The total frequency of HIV-specific IFN-g -secreting CD8+ T cells among PBMC was significantly higher in asymptomatic chronically-infected subjects which reflected the broader response observed.
In chronically-infected subjects, the polyspecificity of the anti-HIV CD8+ T cell responses correlated positively with CD4+ T cell counts (R = 0.5; P=0.004). There was also a trend towards negative correlation between the total frequency of HIV-specific IFN-g -secreting CD8+ T cells and viral load, but it did not reach significance (R = -0.381; P=0.06). In seroconverters, we found no correlation between the parameters of the CD8+ T cell response and the viral load or the CD4+ T cell counts.
Discussion : The most striking fact emerging from this study is that the magnitude of the HIV-specific CD8+ T cell effector activity is much lower in primary HIV-1 infection than in the chronic stage of infection. The polyspecificity of the response was significantly lower in seroconverters than in chronically-infected patients. In addition, the frequencies of CD8+ T cells specific for a given peptide in seroconverters were far less intense than expected, similar to those of chronically-infected asymptomatic subjects and much lower than the frequencies of EBV-specific CD8+ T cells in subjects with infectious mononucleosis.
We found no correlation between the total anti-HIV CD8+ T cell activity and plasma viral RNA or any other clinical or biological parameters during primary infection. It may be difficult to demonstrate any relationship between the viral load and the immune response before a steady-state has been achieved, as suggested by the observations of Musey et al. who found a correlation between the high frequencies of HIV specific CTLp and low plasma HIV RNA only after 6 months of infection.
Conclusion : We have described special quantitative and qualitative features of the immune response of seroconverters that may be responsible for the lack of control of HIV infection. In particular, the number of CTL specificities may be a critical factor for the resolution of infection as recently demonstrated in acute hepatitis C virus infection in chimpanzees. This observation made on the immune response during primary infection should help to improve the design of immunotherapeutic protocols.
Ref: Dalod M, Deschemin JC, Dupuis M, Meyer L, Goujard C, Deveau C, Ngo N, Rouzioux C, Delfraissy JF, Guillet JG, Sinet M, and Venet A. Weak anti-HIV CD8+ T cell effector activity in HIV primary infection. 12th Cent Gardes Symposium, October 25-27, 1999. Paris, France.
In long-term survivors of HIV-1 infection, specific cytotoxic T-lymphocyte (CTL) activity correlates inversely with viral load, according to a report in the September 1st issue of AIDS Research and Human Retroviruses.
Dr. Michael R. Betts, of the University of North Carolina at Chapel Hill, and a multicentre team examined CD4+ cell counts, HIV-specific CTL activity, and viral load over 10 to 14 years in 17 long-term survivors of HIV-1 infection. Long-term survivors experience an average loss of 18 cells per cubic millimeter per year, Dr. Betts' team reports. They point out that in patients with typical progressive HIV-1 infection, 50 to 100 cells per cubic millimeter are lost per year. "In contrast to previous reports," the authors note, "...the viral load in the majority of the [long-term survivors] tested was detectable and, in some [long-term survivors], quite high...and variable over time."
Every long-term survivor studied produced specific CTL responses to Gag, Pol, and/or Env antigens of HIV-1, the results indicated. The investigators propose that the correlation between HIV Gag- and Env-specific CTL activity, and the lack of correlation between Env- and Pol-specific activity or Gag- and Pol-specific activity, suggest that the responses are independently controlled. HIV-1 Pol-specific CTL lytic activity inversely correlated with HIV-1 plasma viral burden, according to the report, while Gag- and Env-related activity were unrelated to viral burden. However, "...the combined effects of HIV-1 Pol- and Env-specific CTL activity [were] a stronger predictor of HIV-1 plasma viral load than the effects of HIV-1 Pol-specific CTL activity alone."
"This correlation suggests that the ability to generate and maintain an efficient HIV-1 Pol-specific CTL response may directly influence the progression rate of HIV-1-infected individuals," the authors conclude." "Further studies will be required," they suggest, "...to determine the association between HIV-1-specific CD4+ T cell-proliferative activity and HIV-1-specific CTL activity in HIV-1-infected individuals, and to correlate these two factors with the control of plasma viraemia in the absence of antiretroviral therapy."
Why long-term survivors are able to show long-term nonprogression is still anyone's guess, according to Dr. Jeffrey Frelinger, one of the coinvestigators from the University of North Carolina at Chapel Hill. "The real value of these results lies in vaccine design, the implication is clear that any therapeutic or prophylactic vaccine should be sure to include a Pol antigen."
Ref: AIDS Res Hum Retroviruses 1999;15:1219-1228. Source: Reuters Health.
An independent Data Safety Monitoring Board (DSMB) composed of European and U.S. scientists recommended that the trial in Spain of RemuneTM (trial 2102) in patients infected with HIV continue to its conclusion. This decision followed review of efficacy data from the trial concerning viral load and CD4 helper T-cell counts.
Professor Edwardo Fernandez-Cruz, Head of the Division of Clinical Immunology at University General Hospital "Gregorio Maranon" in Madrid, and Principal Investigator of the Spanish trial commented, "We are encouraged by evidence of the development of strong immune responses specifically against HIV, including helper T-cell proliferation and cytotoxic T-cell activity." T-cells are believed to play an important role in controlling HIV infection, Professor Fernandez-Cruz explained, because other researchers have noted an association of strong T-cell immune responses in individuals who are infected with HIV but remain long-term nonprogressors. It has become clear that treatment with antiretroviral drugs alone may not prevent the rebound of HIV in some chronically infected patients, and stimulation of the immune system specifically against HIV may be a key to the long term control of HIV replication, Professor Fernandez-Cruz added. Professor Fernandez-Cruz presented immunological data from the trial (which will remain blinded until its conclusion) at The 4th International Symposium of AIDS in Madrid, Spain, November 4-5, 1999.
The Remune (2102) study in Spain is a double blind placebo-controlled trial which enrolled 242 HIV infected patients not taking antiretroviral drugs (ARTs) prior to time of enrollment. The efficacy of Remune administered in combination with ARTs will be assessed by comparing the time to increases in viral load (above 5000 copies/mL) and decreases in CD4 helper T-cell counts between patient groups that received ART plus Remune or ART plus placebo. Several immunological markers of HIV disease progression, such as T-cell proliferation, chemokine and cytokine production (antiviral messengers of the immune system) and cytotoxic T-cells are also being monitored. The trial, being conducted at 13 clinical centers throughout Spain, is expected to conclude in the latter part of 2000.
Source: PRNewswire.
Data presented at the recent 4th AIDS Treatment Project Symposium, November 3rd, Royal College of Physicians, London, showed that patients treated with Remune, an immune-based therapy to treat HIV infection, exhibited a significant increase in lymphocyte proliferation (p<0.05) associated with a decrease in the amount of HIV RNA in the plasma (p<0.05).
"This data would appear to support the premise on which Remune is based, that improved immune health may lead to the control of HIV infection," said Dr. Ronald Moss, The Immune Response Corporation's executive director of medical and scientific affairs, who presented for the Company at the symposium entitled "Immune-Restoration and Immune-Based Therapies: Implications for Concomitant Therapy and Individualised Patient Care." The data presented were based on results from a recently concluded 120-week study that involved 2,500 HIV-infected individuals. Patients were allowed to follow any regimen of antiviral therapy and switch antiviral drugs as needed. In a random, pre-selected cohort (n=252), lymphocyte proliferation was significantly higher (p<0.05) for individuals who received Remune plus adjuvant compared to an adjuvant only control group.
Following treatment with Remune, the data suggest that lymphocyte proliferative responses specifically against HIV may have been restored in these patients. Furthermore, the observed HIV-specific lymphocyte proliferation was associated with control of the virus measured in the plasma of patients. Viral load was significantly lower (p<0.05) in Remune treated patients compared to the control group at multiple time points over the 120-week period. Additionally, there was a significant increase in CD4 cells (p<0.05) in patients treated with Remune.
"The patients in this study were allowed to follow any antiviral drug regimen and switch drugs as often as needed, a situation not typical of most clinical studies in which patients must follow a strictly prescribed regimen. The fact that we still observed significant decreases in viral load for patients treated with Remune against such a background of unrestricted drug therapy is very encouraging in its potential relevance to a real-life clinical situation," Dr. Moss commented.
The data presented were derived from a trial discontinued by the Company based on the recommendation of an independent Data Safety Monitoring Board (DSMB). The DSMB made its recommendation believing that the trial would not be able to demonstrate a statistically significant difference in the number of patient deaths or clinical progression between treatment groups. The 2,500 patient trial (Trial 806) was a multicentre, double-blind, Phase III adjuvant-controlled study in subjects with HIV infection and CD4 T lymphocytes between 300 and 549 cells, regardless of concomitant HIV therapies.
Source: PRNewswire.
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Remune continues to provide evidence of promising effects on the immune system. Clinical data from larger trials and evidence of an influence on treatment suspension or response rates to antiretroviral therapy is now needed. |
French investigators have detected normal production of interleukin-2 (IL-2) by CD4+ T cells in patients with intermediate HIV disease following highly active antiretroviral therapy (HAART).
Dr. Laurence Weiss at Hopital Broussais in Paris and associates prospectively monitored the immune function of 15 patients with intermediate HIV infection who received triple combination antiretroviral therapy. "A progressive increase in both memory and naive CD4+ T cells was observed from the first weeks of therapy, concomitant with a decrease in the expression of activation markers on CD8+ T cells," they report in the October issue of the Journal of Infectious Diseases. After 9 months of HAART, Dr. Weiss' group observed a significant percentage increase in IL-2-producing CD4+ T cells. "In most patients, CD4+ T cells recovered an ability to produce IL-2 on stimulation, similar to that of HIV-seronegative controls."
Despite prolonged viral suppression with HAART, they also found evidence of persistent immune activation. "Overexpression of the early activation marker CD69 on T cells after suboptimal stimulation with soluble anti-CD3 mAB, persisted throughout the 12 months of follow-up," they write. However, Dr. Weiss' group considers the ability of CD4+ T cells to resume production of normal levels of IL-2 to be "remarkable." This is the first report of "...significant improvement in IL-2 production by CD4+ T cells in patients undergoing HAART."
Taken together, these findings indicate that "...immunodeficiency associated with AIDS is reversible, and may be indicative of a long-term clinical benefit in patients with sustained virus suppression."
Ref: J Infect Dis 1999;180:1057-1063. Source: Reuters Health.
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Although the mean value of IL-2 production normalised, normalisation was not universal across all study subjects. Endogenous IL-2 in supraphysiological doses is still likely to have additional effects on lymphocyte proliferation. Additionally, IL-2 acts through the IL-2 receptor present on cell membranes. It is unknown if IL-2 receptor expression (known to be reduced in HIV-disease) was also normalised in these subjects. Daily low dose IL-2 administration has previously been shown to increase IL-2 receptor expression in HIV-infected subjects. |
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PATHOGENESIS
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Researchers studied the kinetics of plasma HIV RNA in patients highly active antiretroviral therapy (HAART) with up to five drugs. The researchers theorized that HIV replication takes place in many local bursts, so while the drugs can reduce the size of bursts, they cannot completely abolish them. After testing the hypothesis using measurements of viral loads and decay rates, the scientists present data indicating that it could be very difficult to eradicate HIV using only drugs. In fact, they say the usefulness of drug therapy at present may be overestimated. According to the authors, "The idea that HIV is produced in multiple, hard-to-abolish, local bursts, whose size is very sensitive to relatively small changes in blocking efficiency ... [suggests that] stimulating all latently infected cells to produce virus under the cover of HAART, with the goal of eradication, may actually result in transmission to new cells." It is possible, however, that transmission could be halted with antiretroviral drugs that are more effective than those currently available.
Ref: Grossman, Zvi; Polis, Michael; Feinberg, Mark B; et al. Nature Medicine (10/99) Vol.5, No.10, P. 1099. Source: CDC HIV/STD/TB Prevention News Update
Researchers from Thomas Jefferson University in Philadelphia investigated whether free virion RNA could be detected in the blood plasma or genital tract fluids of patients undergoing highly active antiretroviral therapy (HAART). The study involved 20 men and two women who were HIV-1 positive and had fewer than 50 copies/mL of HIV-1 RNA in their blood plasma while taking HAART. The authors detected residual viral RNA in the peripheral blood plasma of all 22 patients, suggesting that viral replication is taking place at low levels in each patient. In addition, they found that viral RNA levels were generally lower in patients' genital fluids compared with blood plasma, and in 12 patients they could not be detected. Based on their findings, the researchers concluded that complete cessation of viral replication will most likely require more intense antiretroviral therapies than standard suppressive HAART.
Ref: Dornadula, Geethanjali; Zhang, Hui; VanUitert, Bonnie; et al. Journal of the American Medical Association (03/11/99) Vol. 282, No. 17, P. 1627. Source: CDC HIV/STD/TB Prevention News Update
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In an accompanying editorial Richard D'Aquila and Bruce Walker comment on this study and caution that ..."The finding of residual viral replication in the setting of HAART is not sufficient to change treatment recommendations, particularly when current regimens seem to be successful by measures such as providing persistent augmentation of immunity to CMV and other opportunistic pathogens. The suggestion to intensify treatment regimens will require more data and will require weighing the possible benefits vs toxic effects, tolerability, and interactions of these more complex drug regimens, as well as the ability of patients to adhere to them. It also will be important to determine whether a clinical benefit can be derived from more frequent or sensitive viral load monitoring than is presently standard, although the data from Dornadula et al suggest that clinical trial data should be analyzed using more sensitive viral load assays." |
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They go on to question "...why HAART does not lead to recovery of immune responses to HIV. Numerous studies report that immune responses to HIV-1 decrease with the incomplete suppression of viraemia provided by HAART. These dichotomous responses are not as paradoxical as they may first appear. It can be hypothesized that the level of HIV-1 antigenaemia that occurs when plasma RNA levels are less than 50 copies/mL in plasma is unlikely to be enough to sustain these responses. Indeed, it seems likely that HIV-1 proteins are expressed from only a fraction of the RNA detected in plasma, whereas CMV replication may provide more ongoing antigenic stimulus to drive anti-CMV immune responses. Determining levels of viral protein antigens, as well as RNA, will test this hypothesis." D'Aquila and Walker conclude that..."At this point, HIV eradication is not feasible with chemotherapy alone. However, there are many examples of immune control of persistent viral infections, most notably the herpesviruses. These viruses are not eradicated but are held in check by effective immune responses. Emerging data in HIV infection indicate that some persons achieve immune control of the virus without the need for antiretroviral therapy through persistent HIV-1-specific immune responses. In addition, early treatment of acute HIV-1 infection can lead to marked augmentation of such HIV-specific immune responses. The practical implication of the studies by Dornadula et al and Whitcup et al is that although HAART alone may not be enough to stop HIV replication, it does offer hope for boosting immunity to HIV-1, as already occurs for CMV, thereby providing increased containment of HIV replication. Future efforts need to be directed at developing combination strategies involving both antiretroviral therapy and immunotherapeutic interventions. The next major advances are likely to come from a combination of these 2 approaches. |
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ANTIRETROVIRALS
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New 16-week results from an evaluation of T-20 in an on-going Phase II clinical trial (T-20-205) were presented at the 7th ECCAT. T-20 is a peptide that inhibits HIV AIDS, and is the first member of a new class of investigational antiretroviral compounds known as fusion inhibitors. In this Phase II clinical trial, patients received T-20 (50 mg/twice daily via subcutaneous injection) in combination with individualised oral antiretrovirals. The new results for 55 evaluable patients show that anti-T-20 antibodies do not appear to affect the levels of T-20 in the blood over time, nor the tolerability of chronic T-20 therapy through 16 weeks of treatment. The new data were released as a late-breaker abstract at the Seventh European Conference on Clinical Aspects and Treatment of HIV Infection in Lisbon, Portugal.
These data were gathered specifically to assess the pharmacokinetic and immunological consequences of 16 weeks of T-20 administration to HIV-1 positive adults. Results showed that administration of T-20 by twice daily subcutaneous injection for 16 weeks does not induce the formation of new anti-T-20 antibodies that affect the clearance or elimination of T-20 from the bloodstream. No significant changes in the pattern of circulating levels of anti-T-20 IgG antibody were observed during this period.
Ref: Cohen C et al. Immunologic and pharmacokinetic consequences of chronic therapy with T-20 peptide in HIV-1 positive adults. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection, Lisbon, Portugal, October 23-27, 1999. Abstract 1221. Source: Adapted from a Trimeris release on Business Wire - October 25, 1999
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"The data through 16 weeks show that in addition to having antiviral activity and being well-tolerated, T-20 does not appear to produce an immune response in the body that could theoretically compromise its efficacy," said Dr. Dani Bolognesi, CEO of Trimeris. "This represents an important advance since it shows that since T-20 is a peptide, the body's natural immune system has not altered the drug's bioavailability or compromised its activity against HIV. In addition, the data add to our prior findings that sustained peptide therapy with T-20 could be a viable strategy for treating HIV infection." These subjects had advanced immunodeficiency (median CD4 70 cells/mm3) and relatively uncontrolled viraemia (4.9 log). Given that such subjects are normally unresponsive to vaccination, including adjuvant is it surprising that they failed to mount an antibody response to T-20 within 16 weeks. It remains to be seen if this lack of anti-T20 antibody production would also apply if immune reactivity were greater or when it improves with further treatment. A small trial of T-20 administration to healthy, uninfected subjects should show if they also remain free of antibody production.
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In a separate report Mallinckrodt Inc. announced that it has signed an agreement to supply large-scale quantities of the investigational HIV fusion inhibitor T-20 to Trimeris Inc. If the T-20 peptide is commercialised it could represent the largest volume ever produced for a synthetic peptide of this complexity. Manufacturing limitations are already perceived to be holding back clinical studies and forestall any likelihood of compassionate access. Trimeris is also collaborating with F. Hoffman-La Roche Ltd. to develop and bring to market T-20, which is currently in phase II trials. |
The American Food and Drug Administration (FDA) has refused to grant accelerated approval to the anti-HIV drug adefovir. Adefovir is a nucleotide analogue reverse transcriptase inhibitor that is being studied as second-line therapy for HIV-positive patients who have not responded to antiretroviral therapy (HAART). Early studies of adefovir have suggested that the drug is useful against strains of HIV that have become resistant to ZDV and 3TC. However, the FDA panel responsible for reviewing the data available on adefovir has voted 13 to one against granting accelerated approval. According to the FDA panel, the available data are insufficient to conclude that adefovir is effective and safe at the proposed 60 milligram dose. Adefovir is in fact notorious for its potentially harmful effects on the kidneys. In a pivotal study involving a 120 mg dose of adefovir, as many as 61 per cent of patients had at least one laboratory abnormality indicative of kidney stress. In eight cases, the damage was severe enough to require dialysis.
At present, Gilead Sciences, maker of adefovir, has not issued a press release regarding the FDA decision. The company is expected to make a statement later this week about the status of the adefovir expanded access program as well as the clinical trials currently under way.
Source: "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca"
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A Gilead press release following the FDA committee recommendation indicated that the company would be continuing to work on adefovir to resolve the outstanding issues. Despite problematic toxicities and poor potency at the doses possible in HIV-infection adefovir looks promising for hepatitis B (a 4 log drop in HBV-DNA at 40 mg doses - a good partner for 3TC in this disease?). |
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Perhaps Gilead should now concentrate their efforts on studies and compassionate access to adefovir's sister compound PMPA for HIV-disease. It appears to have improved potency over adefovir and activity against multiply nucleoside resistant virus. Kidney toxicities with this compound have also yet to be seen. |
Agouron Pharmaceuticals has acquired worldwide rights to market Pharmacia & Upjohn's non nucleoside reverse transcriptase inhibitor (nNRTI) delavirdine (Rescriptor). Agouron, a subsidiary of Warner-Lambert Company, is the manufacturer of the HIV protease inhibitor (PI) nelfinavir, the most widely prescribed PI in the US. "The acquisition of delavirdine reflects our commitment to a comprehensive approach to the treatment of HIV infection and AIDS," said Peter Johnson, Agouron's president and CEO. "Agouron has a strong and growing presence in the HIV treatment arena that will be enhanced with the addition of delavirdine, " said Goran Ando, president of Research and Development at Pharmacia & Upjohn. "We believe this agreement represents the best option for the future of the product and is in the best interests of patients."
Whither Tipranavir?
There have been persistent rumors in recent months that Pharmacia & Upjohn wants to divest itself of its entire HIV drug portfolio. Sales of delavirdine have lagged badly behind those of the other nNRTIs, Boehringer Ingelheim's nevirapine and DuPont's efavirenz. In addition to delavirdine, Pharmacia & Upjohn also is developing the drug tipranavir, a potent second generation HIV protease inhibitor that appears to have a favorable resistance profile. Now in Phase I/II studies, tipranavir may benefit individuals who have developed high level resistance to the available PIs. If it is proven safe and effective, tipranavir could emerge as an HIV PI with a unique role. The HIV treatment advocacy community has been in active discussions with Pharmacia & Upjohn regarding an early expanded access program for tipranavir. Such a program is likely to cost more than $10 million. Bringing tipranavir through Phase III trials and FDA accelerated approval will cost millions more. Pharmacia does not appear to have the deep pockets required to bring tipranavir to market.
Now that Agouron has purchased marketing rights to delavirdine, it may be likely that a similar deal is under discussion for the company to take over the development of tipranavir. As a new subsidiary of pharmaceutical giant Warner-Lambert, Agouron is in an excellent position to finance the development of innovative new drugs. Agouron clearly is committed to a bold program in HIV drug development. The company's HIV drug portfolio now includes nelfinavir, delavirdine, and the experimental nNRTI AG 1549, the experimental protease inhibitor AG 1776, and the experimental immune-based therapy Remune.
Source: Ronald Baker, PhD. HIV&Hepatitis.com
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Delavirdine remains without a marketing license in Europe and is currently available through named patient and expanded access studies. We trust that this will continue under Agouron until licensing is obtained.
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US and Italian researchers report in the October 10th issue of AIDS Research and Human Retroviruses that sustained suppression of HIV infection can be achieved with hydroxyurea and didanosine. Dr. F. Lori of the Research Institute for Genetic and Human Therapy at Policlinico S. Matteo, Pavia, Italy, and colleagues point out this combination is "...inexpensive and accessible to the majority of people living with HIV."
Briefly, the team reports in the article that, in 12 HIV-positive patients, treatment with hydroxyurea and didanosine for an average of 122 weeks was associated with "...progressive reduction in viraemia, absence of viral breakthrough in the presence of detectable virus, and induction of an HIV-specific immune response." While they acknowledge that the progressive reduction in viral load observed is "unusual" for two-drug combinations, the researchers say there is evidence that mutant viruses remain sensitive to didanosine in the presence of hydroxyurea. This suggests that it may be possible with a didanosine/hydroxyurea combination to "...[maintain] antiviral response to initial treatment for prolonged periods...and [reestablish] response once resistance has emerged." Dr. Lori's group notes that the patients treated with the hydroxyurea/didanosine combination did not have a "robust" increase in CD4+ T lymphocytes. "However, unlike those patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients," they report.
They conclude, based on this small series of patients, that long-term antiretroviral therapy with a "...simple, well tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters and specific anti-HIV immune responses."
Ref: AIDS Res Human Retroviruses 1999;15:1333-1338. Source: Reuters Health.
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OBSTETRICS & VERTICAL TRANSMISSION
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HIV resistance to lamivudine (3TC) develops rapidly when given with zidovudine in pregnancy
A study published in the November issue of the Journal of Medical Virology suggests that rapid genotypic resistance to lamivudine occurs when the drug is given in combination with zidovudine to HIV-positive pregnant women. The prospective trial involved 14 HIV-infected pregnant women who received zidovudine and five HIV-infected pregnant women who were given zidovudine and lamivudine. Both regimens produced viral load reductions and CD4 cell increases, but the women on the dual therapy saw greater reductions in viral load and larger increases in CD4 cell counts. The researchers note, however, that four out of five of the women receiving both lamivudine and zidovudine had a M184V mutation in the reverse transcriptase gene that is linked to reduced susceptibility to lamivudine at delivery. The study authors concluded that..."zidovudine plus lamivudine reduced HIV-1 plasma viraemia to low levels in pregnant women with advanced HIV-1 disease but the rapid development of genotypic resistance to lamivudine indicates that additional therapy is required both for the long-term benefit of the mothers and to prevent the development of resistant virus that may be transmitted to the infant."
Ref: Clarke JR, Braganza R, Mirza A et al. J Med Virol 1999 Nov;59(3):364-8. Source: CDC HIV/STD/TB Prevention News Update
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This rapid development of resistance is unexpected and is what is seen in other non-pregnant patients administered the dual combination of zidovudine/lamivudine (CombivirTM). Debate continues as to the possible benefit of maintaining the 184V mutation (reduced viral fitness, increased fidelity etc.), but the suppressive potency of 3TC against an unmutated virus is likely to remain more valuable than these theoretical considerations for now.
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The risk of postoperative morbidity following cesarean section is "considerably increased" in HIV-1-infected women, whether or not they are receiving antiretroviral therapy, German investigators report.
While cesarean section can reduce the risk of vertical HIV-1 transmission, the investigators believe that the "...potential risks should be taken into account when counselling HIV-1-positive mothers and when choosing the appropriate mode of delivery." Dr. Thomas A. Grubert and coinvestigators at the Ludwig-Maximilians-University of Munich retrospectively assessed the clinical outcome of 62 HIV-1-infected women who underwent cesarean section between 1987 and 1999. The women were matched with HIV-1-negative controls for age, duration of gestation, and indication for cesarean.
Of the 63 infants born to the HIV-1-infected women, 2 seroconverted, resulting in a 3% transmission rate. In both cases, the mothers had not received antiretroviral therapy. There were no cases of HIV-1 transmission among the women who did receive antiretroviral therapy. "Postoperative complications were significantly more common in HIV-1-positive patients than in their HIV-1-negative matches," the researchers report in the November 6th issue of The Lancet. They add that major postoperative complications were particularly more common. "Especially frequent was severe postpartum fever necessitating antibiotic therapy," the authors write. The HIV-1-infected women were also generally in poorer clinical condition and required a larger number of blood transfusions compared with the controls. Dr. Grubert's group found no significant differences in the rate of postoperative complications between the women on antiretroviral therapy and the untreated women. They also observed no appreciable impact of prophylactic antibiotic treatment on the rate of postoperative complications.
Based on their experience, the researchers conclude that HIV-1-infected women have a "...substantially higher risk of postoperative morbidity..." compared with uninfected women. Therefore, they say, all potential risks need to be considered before a mode of delivery is selected, especially among women on highly active antiretroviral therapy.
Ref: Lancet 1999;354:1612-1613. Source: Reuters Health.
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The additional benefit of cesarean section to the child for mothers with well controlled viral load on combination therapy remains uncalculated but is likely to be extremely low. Given the additional complication rates to the mother as determined in this study mothers and obstetricians should ask informed questions about its routine use. |
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OPPORTUNISTIC EVENTS |
Discontinuation of anti-CMV therapy in HIV-infected patients with CMV retinitis after treatment with protease inhibitors
A study of 14 HIV-infected patients with stable cytomegalovirus (CMV) retinitis sought to determine if discontinuation of specific anti-CMV therapy would reactivate their retinitis or increase their HIV viral load. All of the patients were taking highly active antiretroviral therapy. The results showed that 12 of the 14 patients had signs of immune recovery uveitis before the CMV drugs were discontinued. After CMV treatment was stopped, none of the patients experienced reactivation of the disease or development of extraocular CMV during follow-up of about 16 months. The researchers also note that HIV viral load remained stable after the cessation of anti-CMV medications.
"Prior to the use of HAART, CMV retinitis would progress in many patients despite treatment," said NEI Clinical Director Dr. Scott Whitcup, study chairman and primary author of the JAMA article. "We found that none of the patients in the study had progression of their retinitis, despite being off of standard anti-CMV therapy for an average of 16 months, and in some cases for almost two years. This significant result adds to the body of evidence that some patients who have both CMV retinitis and immune recovery from using highly active antiretroviral therapy may be able to stop their standard anti-CMV medications."
The only people eligible for this trial were those with stable CMV retinitis who had an increase in levels of CD4+ T cell counts to greater than 150 cells per microlitre and had been receiving HAART for at least four months. All 14 patients in the study had their anti-CMV medications stopped. "Although there was no control group, the absence of disease progression in all of the patients is significant, since other well-controlled, randomised clinical trials prior to the use of HAART report that the disease progressed after an average of two months despite anti-CMV therapy," Dr. Whitcup said. "Without anti-CMV therapy, the disease can progress in as little as three weeks."
Despite these positive findings, Dr. Whitcup noted that "to some degree, immune recovery is a double-edged sword. Although we are seeing better control of the CMV retinitis in patients on HAART, we're also seeing more inflammation, or 'immune recovery uveitis,' in these eyes. In patients who took HAART, immune recovery uveitis is seen both in patients who remain on standard anti-CMV therapy and in patients who discontinue anti-CMV therapy. The cause of the inflammation is not clear and requires further study."
Ref: Whitcup, Scott M.; Fortin, Eric; Lindblad, Anne S.; et al. Journal of the American Medical Association (03/11/99) Vol. 282, No. 17, P. 1633. Source: NIH News.
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It is gratifying that this uncontrolled study supports the clinical practice of many HIV specialists in suspending anti-CMV therapy. Opthamological monitoring, however, should continue - perhaps monthly during the first 6 months and every second month thereafter as long as CD4 counts remain above 200/mm3. |
Highly active antiretroviral therapy (HAART) appears to have a positive effect on HIV-associated neurocognitive impairment, Italian researchers report in the October issue of AIDS.
Dr. Valerio Tozzi, of the IRCCS Lazzaro Spallanzani in Rome, and a multicentre team studied 26 patients with advanced HIV infection who had been treated with reverse transcriptase inhibitors for at least 6 months, but were protease inhibitor naive. None of the patients had an opportunistic infection, a confounding neurological illness or a history of drug abuse. The patients were treated with one protease inhibitor, most commonly indinavir, and with two reverse transcriptase inhibitors. Before treatment and after 6 and 15 months of treatment, they underwent 16 standardised tests of mental flexibility, concentration and speed of mental processing, memory, visuospatial and constructional ability, and fine motor functioning.
At baseline, 80.8% of the patients exhibited neuropsychological impairment. The prevalence of impairment dropped to 50% after 6 months of HAART and to 21.7% after 15 months. At both 6 and 15 months, the researchers observed significant improvement in measures of all the areas of neuropsychological functioning. The authors point out that "...the reversibility of neurological dysfunction confirms that viral replication in the brain is necessary to induce clinical and pathological neurological abnormalities." They call for further research "...to correlate clinical and neuropsychological results with virological and pharmacokinetical data within the CNS."
Ref: AIDS 1999;13:1889-1897. Source: Reuters Health.
Highly active antiretroviral therapy (HAART) appears to delay onset of Kaposi's sarcoma treatment failure in HIV-infected patients, according to the results of a retrospective study by UK investigators.
"The immune system plays a central role in the development and control of Kaposi's sarcoma," Dr. Mark Bower of the Chelsea and Westminster Hospital in London and colleagues point out. They therefore speculated that HAART-related immune reconstitution may result in Kaposi's sarcoma regression. To further investigate, Dr. Bower's group retrospectively evaluated a cohort of 78 HIV-infected patients previously treated for Kaposi's sarcoma, who were placed on HAART. The subjects' HAART regimen included a protease inhibitor in 65% and a non-nucleoside reverse transcriptase inhibitor in the remaining 35%. "The median time to treatment failure before starting HAART was 0.5 years," they report in the November issue of AIDS. After HAART was begun, the median time to Kaposi's sarcoma treatment failure was 1.7 years. "This is statistically longer than the time to treatment failure for the same cohort of patients before they started HAART." Fifty-eight percent of the subjects with Kaposi's sarcoma progression had a serum HIV RNA load of greater than 5,000 copies/mL at the time, indicating virological failure of HAART, while 24% of the Kaposi's sarcoma progressors maintained good viral control.
Dr. Bower's group concludes that HAART has a major impact on "...both the epidemiology and clinical progression of Kaposi's sarcoma." In addition, Kaposi's sarcoma progression is not always associated with HAART failure.
Ref: AIDS 1999;13:2105-2111. Source: Reuters Health.
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Interestingly in this retrospective study no difference in the KS protective effect was seen between either PI based and NNRTI based combinations. This was, however, in an analysis based on initial HAART prescribed. It is unknown what the subsequent exposure to PI's might have been in this cohort. It remains to be determined if NNRTI based regimens protect against KS progression equally to that of PI based. |
A sustained increase in the platelet counts of HIV-infected patients with thrombocytopaenia following highly active antiretroviral therapy (HAART) is reported by Spanish investigators.
Dr. Jose Alberto Arranz Caso and colleagues at the Hospital Universitario Principe de Asturias in Madrid describe their experience with 37 HIV-infected patients who had platelet counts of less than 100,000 per cubic millimeter. The subjects received various HAART regimens that included a protease inhibitor. Most (59.5%) received indinavir, 27.0% received saquinavir and 13.5% were on ritonavir. Fourteen patients were also treated with zidovudine, which has previously been associated with transient increases in platelet counts. "After 3 months of highly active antiretroviral therapy, there were significant increases in the platelet count, which were independent of the use of zidovudine and of the baseline platelet count," the researchers report in a letter to the editor in the October 14th issue of the New England Journal of Medicine. "These increases were sustained for at least 6 months." Dr. Caso's group also observed decreases in viral load and increases in CD4 T-cell counts during the follow-up period. Seventy percent of the patients also achieved undetectable levels of plasma HIV RNA. "Linear regression analysis showed no association between the increase in platelet count and the number of CD4 T cells," they write.
Based on these data, the investigators conclude that sustained increases in platelet counts can be achieved with HAART in thrombocytopaenic HIV-infected patients, and that these increases are independent of improvements in CD4 T-cell counts.
Ref: N Engl J Med 1999;341:1239-1240. Source: Reuters Health.
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This study suggests that there is no need to include ZDV in combination regimens for thrombocytopaenic patients. This will be welcome news to those with a history of thrombocytopaenia who tolerate this drug with difficulty.
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Testosterone patch replacement therapy causes menstruation to return in HIV positive women with AIDS-related wasting, according to a report presented at the National Conference on Women and AIDS in Los Angeles. Amenorrhea, or loss of menses, is common among women with HIV. Even in the era of HAART, AIDS wasting (weight loss without an identifiable cause) still occurs, although at a lower rate than prior to HAART. Now, Steven Grinspoon, MD, from Harvard School of Medicine in Boston, Massachusetts, reports that in women with AIDS wasting, the male hormone testosterone is low. Women normally have some testosterone that is secreted by their adrenal glands, on top of each kidney.
Dr. Grinspoon described his study of 45 women with AIDS-related wasting who had a mean body weight that was 91% of normal. In the 15 women who had a daily skin patch with 150 micrograms of testosterone for 12 weeks, the mean weight gain was 1.75 kilograms. That dose was a replacement dose, meaning that it brought blood levels of the hormone into the normal range. There was no change in the weight of the 15 women who wore a placebo patch. Also, the women given the testosterone patch had an increased quality-of-life, as determined by standard questionnaires. Six of the 15 women who had the daily testosterone patch also had no menstruation at baseline. Interestingly, five of those six women had their menstruation return while on testosterone replacement. Dr. Grinspoon did not comment as to whether the women had any side effects from the male hormone, including clitoris enlargement, facial hair or voice deepening. However, this would be less likely if the dose was merely replacement.
Ref: Grinspoon S. Gender specific differences in body composition and glucose metabolism in HIV infected women, the prevalence of hyperinsulinemia and the role of testosterone. Oral presentation at the 1999 National Conference on Women and HIV/AIDS: Navigating into the New Millennium through Collaboration. October 9-12, 1999; Los Angeles, California.
Source: Harvey S. Bartnof, MD. HIV&Hepatitis.com
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OTHER
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US Treatment Guidelines in Spanish
HIV/AIDS Treatment Information Service (ATIS) is pleased to announce that the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents is now available in Spanish.
"Pautas para el uso de agentes antirretrovirales en adultos y adolescents infectados por el VIH" is available in HTML format and in PDF format: http://www.hivatis.org/spanish/publications.html?list
The HTML version is available at:
http://hivatis.org/spanish/guidelines/adult/text/toc.html?list
The PDF version is available at:
http://www.hivatis.org/spanish/guidelines/adult/PDF/A&ANOV2b.PDF
PDF format requires the Adobe Acrobat Reader, which is available from Adobe Acrobat:
http://www.adobe.com/prodindex/acrobat/readstep.html