Medical Consultant
|
ANTIRETROVIRALS |
. The U.S. Food and Drug Administration has approved abacavir (ZiagenTM) for the treatment of HIV in adults and children. Abacavir, an oral medication taken twice daily, is one of a class of medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs) and is taken in combination with other anti-HIV medications. This combination of medicines helps to lower the amount of HIV found in the blood.
The U.S. approval of abacavir is based on results from three phase III studies. In a planned interim analysis at 16 weeks of a study of adults with no previous treatment history, the three drug combination of abacavir/lamivudine/zidovudine was shown to be superior to the combination of lamivudine/zidovudine in reducing HIV-1 RNA viral load. In this study, 75 percent of 87 patients on triple combination including abacavir were at less than 400 copies/mL using the Roche Amplicor HIV MONITOR(r)Test compared to 35 percent of 86 patients on dual therapy. Through 16 weeks of therapy, the median CD4 changes from baseline were 47 cells/mm3 in the group receiving abacavir and 112 cells/mm3 in the placebo group.
In a planned interim analysis at 24 weeks of a study of children with extensive prior nucleoside treatment, the three drug combination of abacavir/lamivudine/zidovudine was shown to be superior to the combination of lamivudine/zidovudine in reducing HIV-1 RNA viral load. In this study, 13 percent of 102 patients on triple combination including abacavir were at less than 400 copies/mL using the Roche Amplicor HIV MONITOR(r)Test compared to 2 percent of 103 patients on dual therapy. After 16 weeks of therapy, the median CD4 increases from baseline were 69 cells/mm3 in the group receiving abacavir and 9 cells/mm3 in the control group. This difference was not statistically significant.
In clinical trials to date, the most commonly reported adverse events were headache, nausea, vomiting, malaise and diarrhoea when abacavir was taken, primarily with lamivudine and zidovudine but also with all marketed and most investigational compounds. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals.
The most serious adverse event associated with abacavir is a hypersensitivity reaction that can be life threatening and has been fatal in some cases. The hypersensitivity reaction has been observed in approximately 3 to 5 percent of patients receiving abacavir in clinical trials and is characterised by fever, skin rash, fatigue, and gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain. The symptoms of this reaction get progressively worse if treatment continues. Patients experiencing these symptoms should stop taking abacavir and contact a physician immediately. Symptoms of this reaction usually occur within the first six weeks of treatment and generally resolve following permanent discontinuation of abacavir. Patients experiencing this reaction must not take abacavir again as restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening and fatal reactions. Glaxo Wellcome will be issuing to patients a Medication Guide for abacavir to provide further information on optimising care with this drug. This may be the first such Medication Guide issued under the FDA's new regulations announced on December 1, 1998.
``Though it only occurs in a small percentage of patients, the potential for a hypersensitivity reaction is something that patients and physicians should be aware of, particularly during the first six weeks of treatment with abacavir,'' said Lynn Smiley, M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome. ``The syndrome is fairly well characterised but much work is being done to better understand the underlying aetiology.'' Abacavir is manufactured and marketed by Glaxo Wellcome Inc.
|
Further studies of triple nucleoside analogue combinations including the ATLANTIC study are due to be reported at the upcoming 6th Conference on Retroviruses and OI's (Chicago, Feb 1 - 5, 1999). If equivalence to PI or NNRTI based combinations (in viral suppression and immune recovery - both functional and numerical) is shown further debate over "which class is first class?". Once through the initial hypersensitivity risk period (up to 42 days) ABC appears well tolerated. As ZDV/3TC dual resistance reduces subsequent response to ABC and the initial mutation selected by ABC is the same as that selected by 3TC (M184V) it seems sensible that these agents are not used together. Data on time to failure, effects in lymph nodes, immune benefits and OI resolution are needed with triple NA combinations (and indeed on NNRTI based combinations) before confidence is established with this approach. |
Alexandra D. Hilts and Douglas N. Fish, of the Denver University Hospital and the University of Colorado Health Sciences Center, respectively, provide an overview of dosage adjustment recommendations based on current research for people with impaired renal or hepatic function taking HIV medications. They note, though, that many of the current medications are very recent and were quickly approved so there may be a lack of information on the subject in some cases. Halving of the zidovudine dosage is recommended due to toxicity issues among patients who have severe renal or hepatic impairment or receive haemodialysis. Similar reductions are suggested for patients on didanosine or zalcitabine, although there are no formal recommendations for dose reduction among patients with hepatic dysfunction. Dosage adjustments should be made based on mean creatinine clearance for patients with renal problems receiving stavudine or patients receiving haemodialysis on stavudine or lamivudine. Patients on stavudine with liver disease should be monitored for toxicity, while pharmacokinetic alterations are likely to be minimal for similar patients receiving lamivudine. Patients on non-nucleoside reverse-transcriptase inhibitors with renal dysfunction do not need dosage adjustment, although patients with hepatic impairment may require a change in dosage. Renal dysfunction or haemodialysis does not require that patients receiving the protease inhibitors saquinavir, ritonavir, indinavir or nelfinavir change their dosage levels. Patients with hepatic impairment should decrease their indinavir dosage. Patients with hepatic dysfunction taking other protease inhibitors may experience drug accumulation, but no recommendations for treatment alteration have been made.
Ref: American Journal of Health-System Pharmacy (01/12/98) Vol. 55, No. 23, P. 2528; Hilts, Alexandra E.; Fish, Douglas N. Source: CDC HIV/STD/TB Prevention News Update
|
Dosage reductions due to decreased drug metabolism must be carefully differentiated from those that may be necessary due to increased sensitivity of an already compromised organ to drug related toxicities. In the first case, dose adjustments guided by pharmacokinetic assessments may be attempted. In the second case the dose adjustments may result in suboptimal doses increasing risk of resistance and should be avoided.
|
Members of the AIDS Clinical Trials Group 175/801 report that therapy with currently recommended antiretroviral drugs for HIV infection could produce symmetrical neuropathy and myopathy. Of nearly 2,500 patients studied, 222 site diagnoses of neuropathy were made, about half of which were cases of distal symmetrical neuropathy. Patients receiving zidovudine and zalcitabine had the highest rates of distal symmetrical neuropathy.
The researchers, who reported their findings in the Dec. 24 issue of AIDS, said that because neuromuscular complications are common antiretroviral therapy-related effects, dose modifications may be required.
Abstract
OBJECTIVE: To determine the frequency of peripheral neuropathy and myopathy in HIV-infected subjects enrolled in a combination antiretroviral treatment trial.
DESIGN AND METHODS: AIDS Clinical Trial Group (ACTG) protocol 175 was a multicentre, double-blind, placebo-controlled, clinical trial. A total of 2467 subjects were randomised to one of four single or combination regimens, containing zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), and their respective placebos. Site investigators reported peripheral neuropathy, and the diagnosis of distal symmetrical neuropathy (DSP) was established by the study authors. Myalgia, muscle weakness and creatine phosphokinase (CPK) were prospectively assessed in a subset of the antiretroviral-naive cohort (n = 1067).
RESULTS: Of 222 site diagnoses of neuropathy, 109 (49%) were DSP. There was a significant difference between treatment arms for rate of DSP and time to first grade 2 or higher DSP (ZDV-ddC, 6%; ZDV, 4%; ZDV-ddl, 4%; ddl, 3%; P = 0.029). Age and Karnofsky score were significant predictors of DSP. Fifty-six (54%) out of 104 patients with DSP remained on study medication at full (n = 29) or reduced (n = 27) dose within 6 months of developing neuropathy. There was no significant difference between treatment arms in the rate of myalgia or muscle weakness. The median CPK of subjects on ZDV-ddC was significantly higher than other study treatments, although CPK levels did not correlate with symptoms of myopathy. Only six subjects were diagnosed with myopathy during the study (one ZDV-ddl, one ZDV-ddC, and four ddl).
CONCLUSIONS: DSP and myopathy may occur with current dosing regimens of combination antiretroviral therapy, and should be diagnosed using stringent criteria. ZDV-ddC was associated with the highest rate of DSP, although features of myopathy were not significantly different between treatment regimens.
Ref: AIDS 1998 Dec 24;12(18):2425-32, Simpson DM, Katzenstein DA, Hughes MD, Hammer SM, Williamson DL, Jiang Q, Pi JT
|
Peripheral neuropathy may be the result of HIV activity as well as drug related toxicity. Indeed, there have been some recent reports of improvements in the symptoms of peripheral neuropathy after initiation of highly active antiretrovirals. Renal Complications of Indinavir Use
|
Researchers at Walter Reed Medical Center in Washington, D.C., report two cases of prolonged indinavir nephrolithiasis in HIV-positive patients who had interrupted indinavir treatment. In the December issue of Clinical Infectious Diseases, Drs. Mark E. Polhemus and Naomi E. Aronson reported that two HIV-positive men who stopped indinavir treatment due to nephrolithiasis still had the problem after six months without the medication. One patient had the kidney stones for 11 months after indinavir treatment was stopped. The researchers note that while indinavir cessation is the conservative treatment for HIV-infected patients with kidney stones, not all cases resolve with conservative treatment, and physicians should strongly consider withdrawing indinavir with any episode of indinavir nephrolithiasis.
Source: CDC HIV/STD/TB Prevention News Update
Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients Abstract
BACKGROUND: Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation.
OBJECTIVE: To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to haemophilia and hepatitis C virus (HCV) infection.
METHODS: Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and haematuria after initiation of therapy, was analysed in relation to haemophilia status and HCV infection.
RESULTS: There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with haemophilia, 50% developed IAN as compared with 17% of patients without haemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for haemophiliacs and 156 (range 5-611 days) for those without haemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02).
CONCLUSION: Overall incidence of IAN was higher than that previously reported and was significantly greater in haemophiliacs than in non-haemophiliacs. HCV may be a contributing factor.
Ref: AIDS 1998 Dec 24;12(18):2433-7 Brodie SB, Keller MJ, Ewenstein BM, Sax PE
Changes in renal function associated with indinavir.
Abstract
BACKGROUND: Indinavir use is associated with a spectrum of renal and urinary tract complications including nephrolithiasis, renal colic and pain without recognisable lithiasis, and a picture of crystalluria-dysuria. A frank nephropathy has not been recognised as part of the spectrum.
METHODS: A retrospective analysis of 106 HIV-infected individuals receiving indinavir was performed with the purpose of identifying the frequency and risk factors for indinavir-associated nephropathy and urinary complications. Individuals receiving ritonavir or nelfinavir served as controls.
RESULTS: A sustained elevation of creatinine (>20%, into abnormal range) was identified in 20 (18.6%) subjects treated with indinavir but not with other protease inhibitors. Creatinine elevation was associated with treatment duration of more than 54 weeks [odds ratio (OR), 7.1; 95% confidence interval (CI), 1.8-27.7], low baseline body mass index < or = 20 kg/m2 (OR, 4.0; 95% CI, 1.0-16.6), and use of trimethoprim-sulphamethoxazole (TMP-SMX; OR, 4.6; 95% CI, 1.5-13.8). Lower urinary specific gravity (P = 0.015), and leukocyturia (P<0.001) were frequently associated features of indinavir nephropathy. No patient developed severe renal impairment and abnormalities were reversible upon discontinuation of the drug. Complications (renal colic, or pain and dysuria) occurred after a mean of 36 weeks (95% CI, 23-48) of indinavir treatment in 13 subjects (12.3%), eight of whom (62%) presented elevated creatinine during follow-up. Only long-term exposure to TMP-SMX (>160 weeks) was identified as a potential risk for the occurrence of a clinical event (OR, 4.7; 95% CI, 1.2-19.2).
CONCLUSIONS: A crystal nephropathy, characterised by serum creatinine elevation, loss of concentrating ability of the kidney, leukocyturia, and renal parenchymal image abnormalities, is a frequent complication of indinavir therapy. Identification of individuals at risk, particularly those with low body mass index or receiving TMP-SMX prophylaxis, may help the decision to initiate indinavir or chose an alternative protease inhibitor in order to minimise renal and urinary tract adverse events.
Ref: Boubaker K, Sudre P, Bally F, Vogel G, Meuwly JY, Glauser MP, Telenti A. AIDS 1998 Dec 24;12(18):F249-54.
|
Many physicians would be reticent to routinely stop indinavir therapy following a single incident of nephrolithiasis. It is helpful that some risk factors have now been identified (as well as the above, increased incidence has been observed in women and during spells of hot weather). Clearly a 20% incidence of renal dysfunction is high and raises concern regarding the long-term safety and utility of indinavir. It should now be investigated as to whether likelihood of such dysfunction increases with length of time receiving this drug. |
Recent studies have suggested significant interactions between protease inhibitor drugs and the multidrug resistance protein MDR1 (also known as P-glycoprotein or Pgp) (Kim, R.B. et al., J Clin Invest, 1998; 101:289-94; Lee, C.G.L. et al., Biochemistry, 1998; 37:3594-601). The protein is a member of the ABC family of transporter proteins, which determine resistance to various chemotherapeutic agents used in cancer treatment.
But now Ranga V. Srinivas and colleagues of St. Jude Children's Research Hospital, Memphis, Tennessee, show that this interaction appears to inhibit the activity of MDR1 and the associated multiple- drug-resistance-associated protein MRP1 in T cells.
"HIV PIs were equally effective against HIV in both wild-type and multidrug-resistant T-lymphocytic cell lines, suggesting that cellular resistance to HIV PIs via activation of an ABC-type drug transporter protein may not be a major therapeutic concern," they concluded.
However, the authors noted that viral resistance to PIs accounts for up to a half of treatment failures. Because of the importance physiologic mechanisms appear to play in this process, they want to be sure their preliminary findings are accurate.
"We are currently investigating whether activation of multidrug transporters plays any role in failure of PI therapy," they wrote.
Source: AIDSWEEKLY Plus; Monday, December 21, 1998 Abstract
The human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) saquinavir, ritonavir, nelfinavir, and indinavir interact with the ABC-type multidrug transporter proteins MDR1 and MRP1 in CEM T-lymphocytic cell lines. Calcein fluorescence was significantly enhanced in MDR1+ CEM/VBL100 and MRP1+ CEM/VM-1-5 cells incubated in the presence of various HIV PIs and calcein acetoxymethyl ester. HIV PIs also enhanced the cytotoxic activity of doxorubicin, a known substrate for MDR1 and MRP1, in both VBL100 and VM-1-5 CEM lines. Saquinavir, ritonavir, and nelfinavir enhanced doxorubicin toxicity in CEM/VBL100 cells by approximately three- to sevenfold. Saquinavir and ritonavir also enhanced doxorubicin toxicity in CEM/VM-1-5 cells. HIV-1 replication was effectively inhibited by the various PIs in all of the cell lines, and the 90% inhibitory concentration for a given compound was comparable between the different cell types. Therefore, overexpression of MDR1 or MRP1 by T lymphocytes is not likely to limit the antiviral efficacy of HIV PI therapy.
Ref: Ranga V. Srinivas, David Middlemas, Pat Flynn, and Arnold Fridland. Antimicrobial Agents and Chemotherapy, December 1998, p. 3157-3162, Vol. 42, No. 12
AIDS patients who have exhausted their treatment options desperately await ABT-378, Abbott's second-generation protease inhibitor. Now their patience is exhausted, too.
A new advocacy group, The Coalition for Salvage Therapy, has sent a letter to Abbott Laboratories demanding that the firm immediately begin trials of the drug in heavily pre-treated patients. The group, made up of a cross-section of patient-advocacy organisations, asserts that Abbott appears to be reneging on an agreement made at the 1998 World AIDS Conference to expedite such studies.
"Almost six months have passed since your initial commitment to conduct such a study and no visible progress has been made," the letter states. "Such delays are unacceptable when people with HIV continue to be at serious risk of illness and death."
The quickest route to approval for new AIDS drugs is to test them in previously untreated patients. Since all anti-HIV medications must be administered in combination with approved antiretroviral drugs, treatment-naive patients are far more likely to respond to all drugs in the combination. But this approach ensures that the patients most eager to receive new drugs - those who have failed previous regimens - are the last to get them.
"Industry must recognise that confining studies to treatment-naive patients in hopes of maximising therapeutic effect for rapid approval is not an option," the latter warns. "Such a strategy will trigger widespread hostility, contentious debate, and closer scrutiny of industry practices in general."
The letter acknowledges that Abbott is experiencing serious production problems with ritonavir capsules. ABT-378 is vastly more effective in combination with ritonavir. But the Coalition asks that studies proceed using the liquid formulation of ritonavir.
The group's focus on salvage therapy is no minor quibble. Despite their efficacy, highly active antiretroviral therapy (HAART) regimens have failed in a growing number of patients. Current salvage therapies offer little in the way of long-term efficacy. These patients thus have their eyes fixed on the drug-development horizon, anxiously awaiting new drugs and new hope.
The letter threatens the fragile peace Abbott recently forged with patient advocates. "Representatives of Abbott have indicated that the company wishes to improve its historically contentious relationship with HIV infected people and their advocates," it notes. "You have expressed a strong desire to create good will and co-operative working relationships with the community. No one wants to see those relationships jeopardised or eroded over this issue, but that surely will happen if evaluation of ABT-378's potential role as salvage therapy is further delayed."
Spearheading the Coalition for Salvage Therapy is Spencer Cox of the New-York-based Treatment Action Group.
Ref: AIDSWEEKLY Plus; Monday, December 21, 1998
|
Many treatment activists have concerns over the expectations raised for drugs in early stages of development. Many now believe that the widespread, early access to lamivudine may have squandered the potential contribution of this drug to future options. The use of lamivudine in dual therapy combinations during compassionate access programmes undoubtedly led to 184 resistant HIV in many individuals. ABT-378 is likely to share broadly similar resistance patterns to the other currently available peptidomimetic protease inhibitors (indinavir, saquinavir, ritonavir, nelfinavir, amprenavir). It's potential activity against such PI resistant HIV is theoretically due to the high blood concentrations of ABT-378 which can be achieved with concurrent ritonavir administration. These higher concentrations may be sufficient to exceed the IC90's of some PI resistance mutations. Less cross-resistance is likely with newer classes of protease inhibitors which are not of the peptidomimetic class (ie. Pharmacia & Upjohns tipranavir, and Bristol Myers Squibbs BMS-232632). These do not occupy the entire protease processing pocket and are therefore less susceptible to interference from shape changes occurring due to mutations (even those away from the active site of the inhibitor). The development and availability of these agents should be pursued with equal zeal to that being expended on ABT-378.
|
Abstract Human immunodeficiency virus type 1 (HIV-1) variants that have developed protease (PR) inhibitor resistance most often display cross-resistance to several molecules within this class of antiretroviral agents. The clinical benefit of the switch to a second PR inhibitor in the presence of such resistant viruses may be questionable. We have examined the evolution of HIV-1 PR genotypes and phenotypes in individuals having failed sequential treatment with two distinct PR inhibitors: saquinavir (SQV) followed by indinavir (IDV). In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under IDV, while few additional mutations emerged. In viruses where no SQV resistance mutations were detected before the switch to IDV, typical SQV resistance profiles emerged following the introduction of IDV. We conclude that following suboptimal exposure to a first PR inhibitor, the introduction of a second molecule of this class can lead to rapid selection of cross-resistant virus variants that may not be detectable by current genotyping methods at the time of the inhibitor switch. Viruses committed to resistance to the first inhibitor appear to bear the "imprint" of this initial selection and can further adapt to the selective pressure exerted by the second inhibitor following a pathway that preserves most of the initially selected mutations.
Ref: Dulioust A, Paulous S, Guillemot L, Delavalle AM, Boue F, Clavel F. J Virol 1999 Jan;73(1):850-854
|
PATHOGENESIS |
In a research study which challenges some of the underlying assumptions of how HIV works to erode the immune system, a team of California AIDS researchers has found the first direct clinical evidence that HIV does more than kill off T cells in the body's immune system. The virus may also prevent the production of new, healthy versions of these vital cells, according to the study.
The scientists -- from the Gladstone Institute of Virology and Immunology at the University of California-San Francisco and from UC-Berkeley -- report the results of their 21-patient study in this month's issue of Nature Medicine.
"These studies focus our attention on the ways that HIV infection might stop the production of new T cells," said Joseph McCune, MD, PhD, senior study investigator and associate professor within the Gladstone Institute at UCSF. "To treat the disease, not only do we need potent antiretroviral drugs to stop the virus from spreading and destroying T cells, we may also need additional therapies to ensure that T-cell production starts anew." The lead investigator for the study was Marc Hellerstein, MD, Ph.D.
The findings are significant in understanding the puzzle of T-cell turnover in the HIV population, an area that has remained controversial among leading AIDS researchers who have proposed different theories to explain why T-cell counts decrease during the course of HIV disease. Scientists use turnover to describe the natural process of T-cell death and new cell production that takes place in all individuals but that is altered after HIV infects the body. The precise mechanism that HIV uses to derail the different parts of this process have been unclear, but the end result is a collapse of the immune system that makes the body vulnerable to the opportunistic infections that cause full-blown AIDS.
Richard Jeffreys, an AIDS treatment activist with New York's AIDS Treatment Data Network, cautions against reading too much into the study's contentions. "From the abstract, it appears that there may be some danger of this study being over interpreted," he wrote to the AIDSACT email discussion group.
"Like the original Ho tap and sink model, the Hellerstein study appears to ignore the shift of T-cells into the lymph tissue, away from the blood. "Although it's not entirely clear from the abstract, my initial impression is that the Hellerstein data could be consistent with the idea that HIV antigens are constantly activating newly produced naive T-cells, thus truncating their lives. Presumably this would show up as a decline in the average life span of T-cells overall. However it pans out, it certainly looks as if a decent model of pathogenesis would factor in all three variables: T-cell redistribution from blood to lymph, T-cell destruction/apoptosis, T-cell production/thymic output."
The results of the new study run counter to the widely held view among AIDS scientists that HIV strikes mainly by killing T cells, the body's front-line defenders, as fast as the immune system can produce them. The controversial new findings include the first direct measurements showing how the human immune system becomes locked in a lethal battle with HIV.
The results challenge a core tenet in the scientific dogma of AIDS, a view that has dominated the field ever since a landmark 1995 study co-authored by famed New York AIDS expert David Ho. The Ho group's research pictured HIV as a virulent attacker that destroys immune cells by the millions, which spurs a flood of new cells --which also become infected and die. In the end, according to this view, the immune system collapses from exhaustion. That leaves the infected victims vulnerable to all the deadly opportunistic diseases that mark the AIDS syndrome.
The new studies indicate that a more important contribution to disease may be the ability to stop T-cell production altogether. Using a new diagnostic tool, the research team determined the rates of production of two types of T cells -- CD4 and CD8 -- that are major players in the immune system and prime targets of HIV. "We found that the virus had an impact on both the rate of T-cell production and the rate of their destruction," Hellerstein said. "But it was the body's ability to produce new cells that was most important in determining T-cell counts." Study participants included both men and women, and all were patients in the General Clinical Research Center at San Francisco General Hospital Medical Center. They represented three groups: HIV-negative and healthy; HIV-positive who had not undergone anti-HIV drug treatment; and HIV-positive who had completed a 12-week course of effective treatment with the potent antiretroviral drugs known as protease inhibitors after previously being untreated.
Major findings include:
Because the labelling was carried out in living people, the results serve as the first direct clinical evidence of cell production in the human bloodstream. In the past, cell generation could not be directly measured in clinical studies because techniques involved radioactive or toxic chemicals unsuitable for human consumption.
Based on the study findings and previous work, McCune said it appears that HIV may disrupt T-cell production in two key ways. First, virus infection may short-circuit the division of memory T cells, whose function is to ward off foreign invaders that the body encountered in earlier years. Without a continuous supply of these cells, the immune system doesn't remember that it can successfully fight off previous enemies and a person becomes susceptible to a variety of infections. Second, virus infection may prevent the production of new T cells from the bone marrow and the thymus, the major organs of T-cell production. In either case, the immune system would collapse and the HIV-infected patient would become immunodeficient, McCune explained.
"It remains unclear whether all HIV-infected patients will be able to increase T-cell production and restore their immune systems after treatment," he said. "For those who cannot, additional therapies may be required."
The California study could prove important in developing new therapies to combat AIDS by jump-starting new T-cell production, researchers said. "These results have important implications on new approaches to therapy aimed at augmenting T-cell production rather than simply blocking T-cell destruction," Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology at the University of California-San Francisco, said in a news release. "They promise to reshape our view of T-cell dynamics in HIV infection."
Dr. Paul Volberding, a veteran AIDS specialist at San Francisco General, called the new cell-tracking system at the heart of the study a "tremendously exciting" tool, because it uses a harmless sugar molecule that can be easily detected in the DNA of the target cells, avoiding the health risks of radioactive or chemical markers in human test subjects. "This gives us a tool we've been waiting for a very long time," Volberding said. Anthony Fauci, head of the infectious-disease branch of the National Institutes of Health and a noted AIDS expert, said the new study is drawing close scrutiny and could be widely influential -- if the results, which run counter to those from other well-respected laboratories, hold up. "This is a controversial area," Fauci said. "I think it will remain a controversial area. It's a good paper, using an interesting technique, but the jury is still out."
An editorial in Nature Medicine portrayed the UCSF-Berkeley study as definitive evidence, but David Ho indicated through a spokeswoman at the Aaron Diamond AIDS research centre in New York that he is not yet convinced. UCSF's Greene, by contrast, called the new study a "paradigm shift."
"This completely alters the way we think about the pathogenesis of AIDS," he said. By all accounts, the AIDS virus infects and kills T cells. The argument is whether that's the main cause of fatal illness or if something else is at play. "This study tells us HIV does two things," said UCSF researcher McCune. "It does destroy cells, but its main affect appears to be on the systems of cell production. What that tells us is that we have to get rid of the virus, no question about that, but we really need to focus our attention on the systems of cell production."
Source: FASTFAX #211, January 8, 1999, published by We The People Living with AIDS/HIV of the Delaware Valley, Inc. http://www.critpath.org/wtp
Researchers from Thomas Jefferson University in Philadelphia, Pa., detected proviral DNA from HIV in the seminal cells of HIV-1-infected men receiving highly active antiretroviral therapy who had no detectable levels of viral RNA in their plasma. The finding suggests that the virus can be sexually transmitted by infected men who appear to be in remission. The researchers, led by Dr. Hui Zhang, found proviral DNA in the seminal cells of four of seven men tested. Two men showed replication-competent viruses in their seminal cells. According to the researchers, "the viruses recovered from the seminal cells had no genotypic mutations suggestive of resistance to antiretroviral drugs and were macrophage-tropic, a feature that is characteristic of HIV-1 strains that are capable of being sexually transmitted."
Ref: Zhang, Hui; Geethanjali, Dornadula; Beumont, Maria; et al. New England Journal of Medicine (17/12/98) Vol. 339, No. 25, P. 1803. Source: CDC HIV/STD/TB Prevention News Update
|
This is also a reminder that the genital tract may remain a sanctuary site for HIV. In an accompanying editorial (Potential for the Transmission of HIV-1 Despite Highly Active Antiretroviral Therapy, New England Journal of Medicine (12/17/98) Vol. 339, No. 25, P. 1846; Haase, Ashley T.; Schacker, Timothy W.) Drs. Ashley T. Haase and Timothy W. Schacker of the University of Minnesota comment on recent findings by Zhang et al. that men receiving highly active antiretroviral therapy and who have undetectable levels of HIV RNA may be able to transmit the virus through sexual contact. Zhang and colleagues detected replication-competent proviruses in the seminal cells of two men. They hypothesise that viral replication might continue in the male genital tract because the blood-testes endothelial barrier may prevent the entry of antiretroviral drugs in high concentrations. They also found that the recovered viruses in seminal cells were still sensitive to antiretroviral drugs and that sequences differed between the recovered viruses found in the peripheral blood and those found in seminal cells. This suggests that latently infected cells from an earlier stage of HIV-1 infection entered and remained in the male genital tract. Haase and Schacker state that while the genital secretions from these patients are not likely to transmit infection since the degree of infectiousness is correlated with the stage of HIV-1 and the levels of the virus and infected cells in the genital tract, efforts to foster preventive behaviour should still be pursued. They assert that sexually transmitted diseases could increase the reactivation of latently infected cells in donor semen and could, therefore, increase incidence. The authors conclude that "it is clearly time not only to renew efforts to prevent sexually transmitted diseases, and to treat them when present, but also, more fundamentally, to increase our commitment to sustain the behavioural and social changes that are the surest guarantee against HIV-1 infection."
|
Scientists previously believed that dual infection with multiple strains of HIV occurred only in rare cases, but new data show that dual-infection cases may be more common than formerly thought. Dr. Patricia Fultz of the University of Alabama in Birmingham, and colleagues investigated HIV-infected chimpanzees that were exposed to an unrelated HIV-1 strain. Using polymerase chain reaction (PCR) tests of cellular DNA from blood and lymph nodes, the researchers found that they could identify the second strain, but only within the first six weeks of exposure to the second HIV strain. According to Fultz, the finding "indicated that the prior infection was downregulating and bringing under control the second strain that the animal was exposed to, which is what you would like in a vaccine." Even universal primers did not pick up the second strain in some animals. Using PCR primers to the strains that had infected the animals, the scientists found that almost every animal was, in fact, infected with a second strain, indicating that primers preferentially pick up one strain. Fultz said she is not optimistic about the ability of existing methods to detect secondary strains.
Source: AIDS Alert (12/98) Vol. 13, No. 12, P. 142
|
The potential for dual infection may also be a mechanism for transmission of drug resistant virus between infected individuals. At the recent Glasgow conference Anders Sonnerberg suggested during a presentation that he has observed this with one couple - the transmission leading to non-response to therapy in the dual/multiply infected partner.
|
Scott J. Brodie of the University of Washington, and colleagues conducted a study providing direct evidence that HIV-specific cytotoxic T cells (CTLs) target HIV replication sites and mediate antiviral activity. The scientists expanded autologous HIV-1 Gag-specific CD8+ CTL clones in vitro and then adoptively transferred the cells to HIV-infected subjects. The transferred cells accumulated adjacent to HIV-infected cells in lymph nodes, producing a transient decline in infected CD4+ T cells. Infected CD4+ T cell resurgence was associated with the disappearance of the transferred cells. The authors note that therapeutic approaches that enhance CTL response to HIV may be useful in the treatment of HIV.
Ref: Brodie, Scott J.; Lewinsohn, Deborah A.; Patterson, Bruce K.; et al. Nature Medicine (01/99) Vol. 5, No. 1, P. 34; Source: CDC HIV/STD/TB Prevention News Update
A fossil retrovirus called HERV-K may possibly help HIV acquire resistance to protease inhibitors, according to some researchers. Fossil retroviruses infected human sperm and eggs millions of years ago, lying dormant in the human genome, although they are sometimes expressed in placental tissue and cancerous tumours. However, a study by Eric Towler of the Science Applications International Corp. in Maryland and German researchers showed that 70 percent of subjects infected with HIV have antibodies to HERV-K. Comparatively, just 3 percent of uninfected people show antibodies to the fossil retrovirus. HERV-K produces a protease that cuts an HIV protein in the same spot as the HIV protease. Towler and colleagues found that the HERV-K protease can enter into HIV in living cells and get transformed into the active enzyme form. Towler suspects that the HERV-K protease, which is highly resistant to drugs, could take over for HIV protease in patients receive protease inhibitors, allowing the virus to replicate long enough to develop resistance mutations. However, Towler cautioned that the idea is still unproved and could very well be wrong. The researchers are currently testing to determine if HERV-K protease can substitute for HIV protease in infected cells.
Ref: Boyce, Nell. New Scientist (19/12/98-02/01/99) Vol. 160, Nos. 2165, 2166, and 2167, P. 21. Source: CDC HIV/STD/TB Prevention News Update
|
VERTICAL TRANSMISSION |
Abstract
OBJECTIVE: To examine the patterns of vertical transmission of zidovudine (ZDV) resistance mutations.
DESIGN: HIV-1 reverse transcriptase codons 10-250 were sequenced from 24 pairs of ZDV-exposed women and their HIV-infected infants as part of the Women and Infants Transmission Study.
METHODS: Viral RNA was extracted from tissue culture supernatants and sequenced using fluorescent dye-primer chemistry and an automated sequencer.
RESULTS: For 17 of these pairs, maternal and infant sequences were identical to one another and lacking known ZDV resistance mutations. The remaining seven maternal sequences contained known mutations associated with ZDV resistance at reverse transcriptase codons 70, 210, 215 and 219. In each case where the maternal HIV isolate showed a pure mutant species, the infant sequence was identical. When the maternal sequence showed the presence of a sequence mixture at codon 70 or 219, the infant's virus showed only wild-type sequence even when the ZDV-resistant mutant was quantitatively dominant in the mother. The single maternal HIV isolate showing mixed sequence at codon positions 210 and 215 transmitted an unmixed mutant to the infant at both positions. When maternal mixtures were present at sites not associated with ZDV resistance, only the dominant species appeared in the infant.
CONCLUSIONS: When maternal HIV isolates contained mixed wild-type and ZDV-resistant subpopulations, only a single component of the mixture could be detected in the infected infants. Resistance mutants without the codon 215 mutation were not transmitted from mixtures, even when the mutants formed the majority of circulating maternal virus. In perinatal HIV transmission, specific ZDV-resistant HIV genotypes circulating in the maternal virus pool may influence whether infection in the infant will be established by a wild-type or ZDV-resistant HIV strain.
Ref: Colgrove RC, Pitt J, Chung PH, Welles SL, Japour AJ. AIDS 1998 Dec 3;12(17):2281-8
|
This study raises important questions with implications for prevention of vertical transmission. Why should 215 mutant virus transmit preferentially, even when a minority species in the mother? |
|
OPPORTUNISTIC ILLNESS |
Researchers from the Amsterdam Cohort Studies on HIV Infection and AIDS report data that "strongly confirm" the causal role of human herpesvirus-8 (HHV-8) in Kaposi's sarcoma (KS). The authors studied over 1,400 homosexual men and more than 1,100 drug addicts to determine the presence of antibodies to HHV-8 antigens. According to the findings, there was a low prevalence of HHV-8 seropositivity among drug users with a low incidence of KS, while the high prevalence of HHV-8 seropositivity among the homosexual men paralleled a high incidence of KS in that cohort. The study was reported in the Dec. 24 issue of AIDS.
Source: CDC HIV/STD/TB Prevention News Update
Multidrug-resistant tuberculosis (MDR-TB) is sweeping through Russia, and health experts note that the country's economic collapse will likely contribute to continued inadequate treatment of the disease. The Centers for Disease Control and Prevention's Dr. Richard O'Brien, one of 10 officials who travelled to Russia earlier this year to assess the problem has called the outbreak possibly "the most severe case of multidrug-resistant TB ever documented." The doctors termed the epidemic "a direct global public health threat" and noted that while the immediate risk to Americans is small, international travel and immigration virtually guarantee that U.S. doctors will encounter MDR-TB from Russia. According to Dr. Michael Kimerling of the University of Alabama in Birmingham, 109,000 new cases of infectious TB were recorded in Russia in 1997, with an incidence rate of 74 per 100,000 people. Among civilians, the rate of drug-resistant TB could be as high as 7 percent of all new infections. In Russian prisons, incidence of infectious TB is thought to be about 4,000 cases per 100,000 population, with up to 20 percent of those infections multidrug resistant.
Ref: Modesto Bee Online (12/31/98); Moran, Mark Source: CDC HIV/STD/TB Prevention News Update
|
Although outbreaks of MDR-TB must be taken seriously where ever they occur, this article displays a somewhat naive and prejudiced attitude on the part of the U.S. commentators. MDR-TB remains endemic in the U.S. itself and does not require "importing" from Russia to become a problem there.
|
Abstract BACKGROUND: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesised that amitriptyline or mexiletine would improve the pain symptoms.
METHOD: A randomised, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit.
RESULTS: The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated.
CONCLUSIONS: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.
Ref: Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, Marra CM, McKendall R, Singer E, Dal Pan GJ, Clifford DB, Tucker T, Cohen B. Neurology 1998 Dec;51(6):1682-8.
|
This is the second trial showing no benefit for amitriptyline. A treatment option with few drug interactions may be gabapentin.
|
Abstract
Hydroxylamine derivatives of sulfamethoxazole may be the reactive metabolites that cause adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMX). The increased frequency of reactions observed in HIV-positive individuals is hypothesised to be due to systemic glutathione deficiency and a decreased ability to scavenge these metabolites. Two hundred and thirty-eight patients were randomised to receive or not receive N-acetylcysteine (3 g of the 20% liquid solution) 1 hour before each dose of TMP-SMX (trimethoprim 80 mg, sulfamethoxazole 400 mg) twice daily, which was initiated as primary Pneumocystis carinii pneumonia prophylaxis. Forty-five patients had to discontinue TMP-SMX within 2 months because of fever, rash, or pruritus including 25 of 102 patients (25%) who were receiving TMP-SMX alone and 20 of 96 patients (21%) who were randomised to TMP-SMX and N-acetylcysteine. The difference between treatment groups is 4% (95% confidence interval [CI]: -16%, +9%). No independent association was found with the hypersensitivity reaction and age, gender, race, HIV risk factor, prior AIDS, concurrent use of fluconazole, or baseline CD4. N-acetylcysteine at a dose of 3 g twice daily could not be shown to prevent TMP-SMX hypersensitivity reactions in patients with HIV infection.
Ref: Walmsley SL, Khorasheh S, Singer J, Djurdjev O. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Dec 15;19(5):498-505
Researchers for the Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group report that the drugs atovaquone and dapsone are similarly effective in the prevention of Pneumocystis carinii pneumonia (PCP) in HIV-positive patients who cannot tolerate trimethoprim-sulfamethoxazole. The researchers, led by Dr. Wafaa M. El-Sadr, suggest that patients receiving dapsone treatment continue usage of the drug; however, they state that atovaquone is better tolerated and may be a more preferable prophylaxis choice. The scientists, who investigated P. carinii pneumonia rates in 1,057 patients receiving either atovaquone or dapsone, found that 122 of 536 patients on atovaquone and 135 of the 521 individuals receiving dapsone developed PCP.
Abstract
BACKGROUND: Although trimethoprim-sulfamethoxazole is the drug of choice for the prevention of Pneumocystis carinii pneumonia, many patients cannot tolerate it and must switch to an alternative agent.
METHODS: We conducted a multicentre, open-label, randomised trial comparing daily atovaquone (1500-mg suspension) with daily dapsone (100 mg) for the prevention of P. carinii pneumonia among patients infected with the human immunodeficiency virus who could not tolerate trimethoprim-sulfamethoxazole. The median follow-up period was 27 months.
RESULTS: Of 1057 patients enrolled, 298 had a history of P. carinii pneumonia. P. carinii pneumonia developed in 122 of 536 patients assigned to atovaquone (15.7 cases per 100 person-years), as compared with 135 of 521 in the dapsone group (18.4 cases per 100 person-years; relative risk for atovaquone vs. dapsone, 0.85; 95 percent confidence interval, 0.67 to 1.09; P=0.20). The relative risk of death was 1.07 (95 percent confidence interval, 0.89 to 1.30; P=0.45), and the relative risk of discontinuation of the assigned medication because of adverse events was 0.94 (95 percent confidence interval, 0.74 to 1.19; P=0.59). Among the 546 patients who were receiving dapsone at base line, the relative risk of discontinuation because of adverse events was 3.78 for atovaquone as compared with dapsone (95 percent confidence interval, 2.37 to 6.01; P<0.001); among those not receiving dapsone at base line, it was 0.42 (95 percent confidence interval, 0.30 to 0.58; P<0.001).
CONCLUSIONS: Among patients who cannot tolerate trimethoprim-sulfamethoxazole, atovaquone and dapsone are similarly effective for the prevention of P. carinii pneumonia. Our results support the continuation of dapsone prophylaxis among patients who are already receiving it. However, among those not receiving dapsone, atovaquone is better tolerated and may be the preferred choice for prophylaxis against P. carinii pneumonia.
Ref: El-Sadr, Wafaa M.; Murphy, Robert L.; Yurik, Teresa McCabe; et al. New England Journal of Medicine (12/24/98) Vol. 339, No. 26, P. 1889.
|
OTHER NEWS |
The Office of Dietary Supplements (ODS) at the U.S. National Institutes of Health has announced the launch of its new International Bibliographic Information on Dietary Supplements (IBIDS) database.
IBIDS is a database of published, international, scientific literature on dietary supplements that is available to the public free of charge through the ODS Internet home page (http://dietary-supplements.info.nih.gov). The purpose of this database is to assist both scientists and the general public in locating credible, scientific literature on dietary supplements. The computer interface was designed to be user-friendly so individuals with all levels of expertise may use it easily. For those unfamiliar with dietary supplement terminology, a drop-down list of standard keywords is available.
IBIDS is driven by a sophisticated search strategy that simultaneously and transparently searches numerous existing medical, botanical, agricultural, chemical and pharmaceutical databases. This presented a technical challenge because each of the existing databases uses a different format and set of key words.
|
ATP DR FAX SYMPOSIUM II NEW HIV TREATMENTS: IMPLICATIONS FOR CLINICAL PRACTICEA One Day Symposium AIDS Treatment Project and the 'Doctor Fax' is hosting a one day symposium on new HIV treatments and their implications for clinical practice. This is an international meeting intended for HIV treating clinicians, researchers, health commissioners and purchasers. DATE: Thursday 25 February 1999 INVITED SPEAKERS INCLUDE: Dominique Costagliola (France), Heather Leake (UK), Marty Markowitz (USA), Francis Rotblatt (UK) Programme will include discussion of new treatments: FTC, MKC-442, ABT-378, new capsule ritonavir, efavirenz, 3 newer NNRTI's, abacavir, amprenavir, enteric coated ddI, adefovir, T-20, tipranavir, F-ddA. PLACES STRICTLY LIMITED: For further information or to confirm attendance please call Raffi Babakhanian or Yasmin Motala, ATP, 0171 407 0777
|