Medical Consultant
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TREATMENT STRATEGIES
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Paul Blanchard, ATP.
On-off, intermittent or pulsed therapy is currently being explored within research settings. Toxicity and tolerability issues with currently available antiretrovirals mean that many who would happily take these drugs in the medium term are seriously questioning their ability to maintain this intake for decades, or even the rest of their lives. The real difficulties in achieving viral eradication now having hit home, the researchers also realise the problems inherent with long-term administration of these agents. Long term administration, is of course, only a possibility if successful viral suppression and lack of emergence of resistance can also be maintained.
Using the host immune system as an additional suppressive pressure on viral replication is perhaps the most attractive option to allow rest periods from antiviral drug administration. Researchers have speculated for some time that restoration of an immune state resembling that found in long-term non-progressors may allow suspension of antiretroviral therapy with control of viraemia maintained.
Gabriel Ortiz and Douglas Nixon of the Aaron Diamond Research Center, New York, describe the virological and immunological events accompanying both intermittent and discontinued antiretroviral therapy in a recent paper published in The Journal of Clinical Investigation.
Six patients were identified who had experienced difficulties with their adherence to antiretroviral therapy. Theses difficulties led to intermittent pill taking and periods where the regimens were discontinued altogether. Five of the subjects had been enrolled into studies providing therapy within 4 months of primary infection with HIV; the 5th subject had been chronically infected for approximately 27 months before receiving treatment. All received combination therapy including both single or double protease inhibitors and 2 nucleoside analogues.
In addition to levels of viraemia, HIV-1 specific immune responses were measured in these 6 subjects. HIV-1 specific cytotoxic lymphocyte precursor (CTLp) frequency and ELISPOT for quantifying cytokine release from antigen specific CD8+ T cells gave a measure of the strength of CTL response. Binding antibody titres and neutralisation assays were performed as a measure of humoural response.
Even though most patients who stop combination antiretroviral therapy experience a rapid viral rebound, three of these six subjects continued to suppress HIV plasma viraemia for between 4 and 24 months after discontinuation. The other 3 subjects failed to contain plasma viraemia and experienced rapid rebound in viral load. Results are presented for the specific immune responses measured during the course of their full, intermittent or suspended therapy.
The investigators found that the most striking association with suppression of plasma viraemia after antiretroviral cessation was the presence of broad and strong HIV-1 specific immune responses. This association was particularly clear for the anti-HIV CTL responses. The dilemma is, however, that the maintenance of these immune responses appears to depend on antigenic stimulation. The responses were stimulated during the reappearance of viraemia during poorly adherent or suspended periods. These responses decline during highly suppressive combination antiretroviral therapy.
As the authors state... "In the subjects studied here, intermittent adherence to the drug regimen appeared to stimulate HIV-1 specific immune responses, even at low levels of plasma viremia. Their intermittent adherence seems to have boosted their immune responses by providing a low but sufficient level of antigen". The autoimmunisation by antigens produced during periods of incomplete suppression acted as a powerful stimulus to boost CTL and antibody responses in these patients.
The three patients who successfully suspended drug therapy and who exhibited these strong anti-HIV immune responses were all treated in early infected. The one chronically infected individual in this study did not develop such responses during intermittent adherence and experienced rapid viral rebound on stopping therapy. HIV-specific CD4 helper T lymphocyte responses were not measured in this study and it remains unclear what their role might be in the stimulation of these cytotoxic and humoural responses.
Ref: J Clin Invest, September 1999, Volume 0, Number 1999, 07371-R18 Full paper available at: http://www.jci.org/cgi/content/full/199907371 Unfortunately the majority of patients who are poorly adherent to antiretrovirals are not rewarded with boosted immunity. Viral resistance and further immune suppression is the usual outcome of missed or inconsistent dosing.
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Stop-start strategies of autoimmunisation may also foster resistance due to replication of HIV in the face of sub-optimal drug pressure while drug levels are ramped up or down during each stop or start. This is further compounded by differential half-lifes allowing periods of dual and monotherapy with certain regimens. A safer strategy would be to boost HIV-1 specific immune responses in antiretroviral treated individuals by providing exogenous antigenic stimulation in the form of therapeutic immunisation. All promising vaccine candidates, even those intended as preventative, should now be tested in this setting as a matter of urgency. It appears that their support may be of necessity for the long term durability and tolerability of antiretroviral combinations. |
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IMMUNOLOGY
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The ex vivo antiviral CD8+ repertoires of 34 human immunodeficiency virus (HIV)-seropositive patients with various CD4+ T-cell counts and virus loads were analysed by gamma interferon enzyme-linked immunospot assay, using peptides derived from HIV type 1 and Epstein-Barr virus (EBV). Most patients recognised many HIV peptides, with markedly high frequencies, in association with all the HLA class I molecules tested. We found no correlation between the intensity of anti-HIV CD8+ responses and the CD4+ counts or virus load. In contrast, the polyclonality of anti-HIV CD8+ responses was positively correlated with the CD4+ counts. The anti-EBV responses were significantly less intense than the anti-HIV responses and were positively correlated with the CD4+ counts. Longitudinal follow-up of several patients revealed the remarkable stability of the anti-HIV and anti-EBV CD8+ responses in two patients with stable CD4+ counts, while both antiviral responses decreased in two patients with obvious progression toward disease. Last, highly active antiretroviral therapy induced marked decreases in the number of anti-HIV CD8+ T cells, while the anti-EBV responses increased. These findings emphasise the magnitude of the ex vivo HIV-specific CD8+ responses at all stages of HIV infection and suggest that the CD8+ hyperlymphocytosis commonly observed in HIV infection is driven mainly by virus replication, through intense, continuous activation of HIV-specific CD8+ T cells until ultimate progression toward disease. Nevertheless, highly polyclonal anti-HIV CD8+ responses may be associated with a better clinical status. Our data also suggest that a decrease of anti-EBV CD8+ responses may occur with depletion of CD4+ T cells, but this could be restored by highly active antiretroviral treatment.
Ref: Marc Dalod, Marion Dupuis, Jean-Christophe Deschemin, et al. Journal of Virology, September 1999, p. 7108-7116, Vol. 73, No. 9.
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ANTIRETROVIRALS
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In North America, Western Europe and Australia, protease inhibitors are credited with reducing the number of deaths due to AIDS. However, these drugs are associated with many side effects, including changes in body shape. Now, doctors in France have reported cases of hair loss in patients taking the protease inhibitor indinavir (Crixivan).
The doctors documented hair loss in ten men aged 30 to 51 years who had an average CD4+ cell count of 243. Seven patients had a viral load below 200copies; the three remaining patients had viral loads ranging between 320and 47,000 copies. All patients were receiving triple anti-HIV drug therapy that included indinavir.
The patients noticed their hair loss during the first six months of therapy. According to the report, "almost complete hair loss" was experienced in various parts of the body in the following proportions: lower legs (10 patients), thighs (eight), pubic area (five), chest (three) and head (two). Interestingly, hair loss from the scalp was not as severe as in other parts of the body. In addition to hair loss, eight patients out of 10 experienced dry skin. The patients' hair regrew within four months after patients exchanged indinavir for other protease inhibitors, including nelfinavir and ritonavir/saquinavir. In other cases, indinavir was replaced by the non-nucleoside analogues nevirapine or efavirenz. The French researchers speculate that indinavir may interfere with vitamin A-like molecules in the body and that this interference may be linked to the hair loss experienced by some people. This link, however, remains theoretical.
Ref: New England Journal of Medicine 1999; 341(8): 618. 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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Hair loss has also been reported with 3TC use and hydroxyurea use. Anecdotal patient reports of hair regrowth occurred during an indinavir to efavirenz switching study for lipodystrophy. |
The risk of developing nephrolithiasis related to use of HIV protease inhibitors increases as the environmental temperature rises, according to investigators in Barcelona.
It is recommended that patients drink at least 1.5 L of water a day to reduce the risk of developing protease inhibitor-related nephrolithiasis, the Spanish team explains. However, during the summer months, they noticed that the incidence of nephrolithiasis increased among HIV-infected patients receiving indinavir, even among those compliant with water intake.
To further investigate, Dr. Esteban Martinez and colleagues at the Institut d'Investigacions Biomediques evaluated the 1-year incidence of nephrolithiasis in 758 HIV-infected patients treated with indinavir. During the study period, 326 episodes of nephrolithiasis developed in 103 patients. "The overall incidence ranged from 0 to 10.2 episodes per 100 patients exposed per month," the researchers report in the August issue of Clinical Infectious Disease.
Dr. Martinez's group found a "...significant correlation between temperature and the overall incidence of nephrolithiasis and the incidence of recurrences but not with the incidence of first episodes." Conversely, they observed no relationship between nephrolithiasis and humidity or atmospheric pressure. "The higher incidence of nephrolithiasis during hotter months did not seem to be due to a lack of compliance with water intake," they add.
Dr. Martinez's group concludes that a subgroup of HIV-infected patients are at increased risk of indinavir-related nephrolithiasis and the "...risk for those patients increases proportionally with temperature."
Ref: Clin Infect Dis 1999; 29:422-425. Source: Reuters Health
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Climatic influences were also reported in 1997 observed in indinavir patients in Florida. High regional incidences which may depend on local drinking and eating habits are now further compounded by seasonal variations difficult to control by even well informed patients. Improved PK characteristics with lower peak levels of indinavir may reduce the risk of crystalluria and kidney stones and can be achieved by coadministration with ritonavir. Such coadministration might be a serious consideration in "difficult" climatic regions over and above the benefits of reduced frequency of dosing and elimination of the need for fasting. |
A "strong temporal association" between the development of junctional bradycardia symptoms and treatment with the HIV protease inhibitor nelfinavir is described by two physicians in Boston, Massachusetts. Based on this case, they recommend that "...nelfinavir should be considered as a potential cause of cardiac symptoms in patients with HIV disease."
Because of virologic failure on three-drug antiretroviral combination treatment, a 45-year-old HIV-infected man was switched to a four-drug combination regimen, Drs. Raphael J. Landovitz and Paul E. Sax of Brigham and Women's Hospital explain. Previously treated with indinavir, stavudine, and lamivudine, the patient was put on nelfinavir, saquinavir, nevirapine, and lamivudine. "Twelve hours after taking his first dose, the patient noted a 'skipping heartbeat,'" they report in the August issue of Clinical Infectious Diseases.
The patient appeared well and had no cardiac history or family history of arrhythmia or sudden death, and the physicians identified no apparent factors to explain the patient's symptoms. Electrocardiography "...showed a high junctional rhythm at 56 beats/min and no ST-T wave abnormalities." Echocardiography indicated an "...ejection fraction of 62% without wall motion abnormalities."
The patient's symptoms ceased 24 hours after all antiretroviral drugs were discontinued, and he remained asymptomatic for 2 weeks. The symptoms recurred after treatment with nelfinavir alone was resumed. No cardiac symptoms developed over the next 20-month period after the patient was switched to a regimen of didanosine, nevirapine, ritonavir, saquinavir, and hydroxyurea. Based on these observations, the physicians conclude that "...nelfinavir was the most likely aetiology of junctional bradycardia."
Ref:Clin Infect Dis 1999;29:449-450. Source: Reuters Health
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Even though the rechallenge with nelfinavir monotherapy may have helped establish the cause of this patients bradycardia it is a shockingly dangerous practise in someone who was switching therapy due to failure of a previous PI containing regimen. Lets hope the bradycardia returned to establish the diagnosis before further evolution of PI resistant virus while on nelfinavir monotherapy! |
Abacavir, the first clinically available guanosine analogue HIV-1 reverse transcriptase inhibitor, used in combination with mycophenolic acid, results in a potent and synergistic inhibition of HIV-1 replication in vitro "...to an extent not previously observed with other antiretroviral combinations."
"The use of inhibitors of purine nucleoside metabolism has been advocated for the treatment of HIV-1 infection," Dr. David Margolis of the University of Maryland Institute of Human Virology in Baltimore and colleagues explain.
Mycophenolic acid, which is used in organ transplantation, is a specific inhibitor of lymphocyte proliferation via blockade of purine synthesis. Specifically, this agent "...acts on inosine monophosphate dehydrogenase to block conversion of inosine monophosphate to guanosine monophosphate." "Because of the antiviral potency of abacavir and the lymphocyte specificity of [mycophenolic acid], we hypothesised that these drugs might synergise in the inhibition of HIV replication without causing substantial cellular toxicity."
Overall, the combination of these two drugs in vitro was "...exceedingly potent and synergistic," the researchers report in the August 15th issue of the Journal of Acquired Immune Deficiency Syndromes.
The antiviral activity of abacavir was "greatly enhanced" by low concentrations of mycophenolic acid in activated peripheral blood mononuclear cells and monocyte-derived macrophages. "This effect was also seen when primary clinical isolates were used." Dr. Margolis 'team also found that this combination was active against an HIV-1 strain that encoded the M184V mutation. "However, the combination of [mycophenolic acid] and zidovudine (ZDV) or stavudine (d4T) was antagonistic," they note.
This salvage therapy approach is currently being pursued at the University of Maryland in a small, uncontrolled pilot study with "...patients who essentially have no other viable therapeutic options." The patients have only been on therapy for a few weeks, Dr. Margolis explained, but the "...very, very early results are somewhat encouraging."
Ref: J Acquir Immune Defic Syndr 1999; 21:362-370. Source: Reuters Health
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These are similar mechanisms to the synergism seen between some nucleoside analogues and hydroxyurea. Mycophenolic acid is currently licensed in the UK for use in oncology. The minimum dosages required for this effect should now be established as this interaction may need to be exploited in the very near future for salvage therapy situations. |
A study by physicians at the University of Maryland in Baltimore reveals that while highly active antiretroviral therapy (HAART) is effective in children who can tolerate it, the success of the treatment depends on adherence to the regimen. The researchers, who report their findings in the August issue of the Pediatric Infectious Disease Journal, studied 72 perinatally infected children taking a HAART regimen that included a protease inhibitor. Of the 42 patients who were adherent, 52 percent achieved and maintained undetectable viral loads; however, viral loads of less than 400 copies/mL were only achieved in 10 percent of non-adherent patients. The children were considered adherent if at least 75 percent of all their antiretroviral drug prescriptions were filled.
Source: CDC HIV/STD/TB Prevention News Update
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OPPORTUNISTIC EVENTS
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Mortality is higher among AIDS patients who are hospitalised in institutions with less experience in treating patients with HIV infection compared with patients treated in hospitals that care for greater numbers of AIDS patients. A group of California-based researchers, led by Dr. William E. Cunningham at the University of Los Angeles School of Public Health, evaluated the hospital discharge records for adults with AIDS in 1994 for all 333 acute care hospitals in California.
"Among 7,901 persons hospitalised with AIDS, the unadjusted inpatient mortality was 9.0%," Dr. Cunningham's group reports in the August issue of the American Journal of Medicine. "The adjusted mortality rate varied significantly from 12.4% among institutions with the lowest quartile of AIDS experience to 10.3%, 6.3%, and 7.3% by quartile of greater AIDS experience."
Patients with more severe illness, co-morbidities and prior hospitalisations also had a significantly increased risk of mortality. However, there was no relationship between mortality and sex, race or insurance status. These results complement the findings of other studies performed in the 1980s, the investigators add. "It is striking that, despite policy recommendations to establish state wide and regional networks and discussion of a concerted effort to enhance provider networks and education, few changes in service delivery were achieved on the basis of those findings."
Dr. Cunningham's group therefore believes that "...the time has come to implement policies to direct patients with AIDS to hospitals and providers with sufficient AIDS experience."
Ref: Am J Med 1999; 107:137-143. Source: Reuters Health
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Similar findings have previously been reported for cancer surgery, organ transplantation and ongoing care for patients with myocardial infarction. The experienced and motivated doctor with quality support is clearly the better choice in potentially life-threatening illnesses - no surprise here really. |
In March of this year, the U.S. Public Health Service and the Infectious Diseases Society of America reconvened the Prevention of Opportunistic Infections Working Group to review current recommendations for the prevention of opportunistic infections (OIs) in people infected with HIV. Members of the OI Working Group include representatives from federal agencies, universities, professional societies, community health-care providers and patient advocates. Primary changes in the recommendations include: the addition of statements concerning discontinuation of prophylaxis against specific OIs when the CD4+ T-lymphocyte count increases in response to HAART; new recommendations regarding human herpes virus type 8 and hepatitis C virus; new recommendations concerning injection drug users; new recommendations about short-course chemoprophylaxis against TB in HIV-infected people with positive tuberculin skin tests; changes in secondary prophylaxis (chronic maintenance therapy) recommended to prevent the recurrence of Mycobacterium avium complex and cytomegalovirus disease; caution against using fluconazole during pregnancy; and statements concerning the use of varicella and rotavirus vaccines among HIV-infected infants. Because new information on the prevention of OIs is emerging and research for OI prophylaxis is ongoing, the OI Working Group has developed a mechanism for routinely and periodically reviewing emerging data and for updating these guidelines on a regular basis. The most recent information will be available from the ATIS website.
Ref: Morbidity and Mortality Recommendations and Reports (20/08/99) Vol. 48, No. RR-10, Source: CDC HIV/STD/TB Prevention News Update Full Text available at: http://www.hopkins-aids.edu/treatment/index_treat.html
The incidence of cytomegalovirus (CMV) retinitis is significantly reduced among HIV-infected patients treated with protease inhibitors, according to researchers who attribute these effects to improved immunologic status.
In a prospective, multicentre study, members of the Spanish CMV-AIDS Study Group evaluated a cohort of 172 HIV-infected patients with baseline CD4 cell counts less than 100/µL. Dr. Jose L. Casado of the Ramon y Cajal Hospital in Madrid and co-investigators monitored CMV status, CD4 cell count, and HIV load in the subjects following the initiation of protease inhibitor therapy.
"The cumulative incidence of CMV retinitis was 5% at 1 year and 6% at 2 years," they report in the August 20th issue of AIDS. The only factor associated with risk of CMV retinitis was a positive CMV polymerase chain reaction (PCR) test result when therapy was begun. For those testing positive for CMV at baseline, the 12-month CMV retinitis event rate was 38% compared with 2% among those testing negative for CMV at baseline. "Only 2% of patients remained CMV PCR-positive after 3 months of protease inhibitor therapy, and CMV viraemia was not associated with a worse therapy response or shorter survival."
Dr. Casado's group points out that the 2-year cumulative incidence (6%) of CMV retinitis for these patients was "...significantly lower than the 20-28% at 1 year reported in recent studies for a similar population of patients not receiving protease inhibitor therapy." It is also lower than the 1-year CMV event rate of 14% reported in a CMV prophylaxis study in which the subjects received oral ganciclovir.
The investigators believe that these findings "...offer a new approach to the management of CMV disease in HIV-positive patients, where prevention strategies could be implemented during a short period after the initiation of protease inhibitor therapy."
Ref: AIDS 1999; 13:1497-1502. Source: Reuters Health
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The implications of this observational study may be to treat patients with <100 CD4 cells with potent antiretroviral therapy including at least one PI and have opthalmological checks every 4-8 weeks until the CD4 count is substantially above the 100 cells/mm3 level. It remains unclear if CMV-PCR positive patients would benefit from additional pre-emptive anti-CMV therapy in addition to potent antiretrovirals while CD4 counts are rising. |
Dr. Isabelle Cochereau and colleagues from the Hopital Bichat have determined that highly active antiretroviral therapy (HAART) reduces the percentage of patients with HIV-related cytomegalovirus (CMV). Reporting in the August issue of the American Journal of Opthamology, investigators studied the rate of HIV-related CMV in patients between 1995 and 1997. Cases of newly diagnosed HIV-related CMV dropped from 6.1 percent in 1995 to 1.2 percent in 1997. In addition, they found that average CD4+ cell count in patients with CMV retinitis was higher, and the rate of relapse was lower in 1997.
Source: CDC HIV/STD/TB Prevention News Update
Researchers from Duke University in North Carolina performed a cross-sectional study to determine clinical factors correlated with yeast colonisation of the oropharynx in people with HIV. Investigators studied five variables, including: CD4 lymphocyte counts, plasma HIV-1 RNA levels, history of prior fungal infections, number of antiretroviral agents used, and prophylaxis for Pneumocystis carinii pneumonia. Researchers found that 70 percent of patients were colonised with yeast, and that the only significant correlate was with HIV-1 RNA levels. Writing in the August issue of the Journal of Infectious Diseases, investigators conclude that decreases in oropharyngeal yeast may be achieved without specific antifungal therapy.
Source: CDC HIV/STD/TB Prevention News Update
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IN BRIEF
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Members of the Women and Infants Study Group examined the relationship between vitamin A deficiency and the risk of vertical HIV-1 transmission. The study involved 449 HIV-1-infected women who had their vitamin A levels measured during the third trimester of pregnancy. The researchers, who report their findings in the August issue of Clinical Infectious Diseases, found no statistically significant link between mother-to-infant HIV-1 transmission and vitamin A levels. The team, led by Dr. David N. Burns of the National Institute of Child Health and Human Development, did note that women with low and very low levels of vitamin A prior to the third trimester had a greater risk of delivering babies with low birth weight than those who had higher vitamin A levels.
Source: CDC HIV/STD/TB Prevention News Update
Scientists have determined that the first recorded AIDS case in the United States was that of a teenage prostitute who died 1969. Frozen tissue samples of the 15-year-old, who died from Kaposi's sarcoma, revealed HIV antibodies. The findings, presented at the 11th International Congress of Virology in Sydney, suggest that strains of HIV may have been dormant for years before evolving into the disease as it is now known.
Source: CDC HIV/STD/TB Prevention News Update
San Francisco public health officials have linked a syphilis outbreak in the city to an America Online chat room. According to the experts, the outbreak was traced to at least seven men who met through the SFM4M (San Francisco Men for Men) chat room. Dr. Jeffrey D. Klausner, director of the San Francisco Department of Public Health's sexually transmitted diseases division, is launching an online awareness and education program in the chat room and through PlanetOut, the largest online service for gays and lesbians. Statistics show that San Francisco saw a 33 percent decline in reported cases of syphilis during the first six months of this year compared to the first half of 1998. However, while health officials usually use "contact tracing" to identify and warn the sex partners of syphilis patients, the situation is difficult for patients who meet on the Internet because they generally only know each other by their screen names.
Source: CDC HIV/STD/TB Prevention News Update
The British High Court will decide this week whether local authorities have the right to force two parents to have their baby tested for HIV. The infant's mother is HIV-positive and has known her own HIV status for several years. The parents, who are strong believers in alternative medicine, feel that if the child tests positive for HIV, they will not be able to direct her treatment. In addition, the child's father believes she may be stigmatised if she tests positive. Local authorities believe the HIV test should be performed so the child can receive the best possible care, if she is found infected.
Source: CDC HIV/STD/TB Prevention News Update