Contents
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DHHS (US) Updated Guidelines Published
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5-drug regimen provides improved initial suppression of HIV-1 replication over triple
therapy
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A review of current knowledge on the new (soft gel) form of saquinavir
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Adefovir dipivoxil - new results with hepatitis B and HIV
-
Nevirapine and rashes
-
Lamivudine-induced paronychia
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Protease inhibitors prolong survival in AIDS patients with CMV retinitis
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Progression of CMV retinitis may indicate inadequate ganciclovir maintenance
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Intravenous cidofovir for the treatment of relapsing CMV
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Failure of cytarabine in progressive multifocal leukoencephalopathy
-
Intracranial tuberculoma may be exacerbated by HAART
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Weight loss directly related to plasma HIV load
-
Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry
-
High-intensity exercise does not increase HIV load
ANTIRETROVIRAL TREATMENT GUIDELINES AND STRATEGIES
DHHS (US) Updated Guidelines Published
The third revision of the Guidelines for Use of Antiretroviral Agents in Adults and
Adolescents from the Department of Health and Human Services (US) has been published
in the 24th April issue of MMWR (Mortality and Morbidity Weekly Report). This important document
is also available in full on the Internet in plain html format at:
http://www.healthcg.com/hiv/nihreport/guide
Or in Adobe's portable document format (pdf) at:
http://www.atis.org/
The Guidelines are the product of a 35 member Panel composed of HIV care providers,
HIV investigators, consumer advocates and relevant federal agencies (CDC, NIH, FDA,
HRSA, and HFCA).
It is important to acknowledge that the Panel responsible for the DHHS Guidelines
has established a mechanism to update the Guidelines to reflect the rapid evolution
of recommended management strategies. This is done by a monthly telephone conference
of a 15 member Panel Subcommittee using a prepared agenda. Topics may be suggested from
any Panel member and are then assigned to a Panel discussant to lead the conference
review that may include external invited experts. Decisions by the Panel Subcommittee
are by majority vote at roll call; affirmative decisions are then sent to the full Panel
for final vote.
This is the third revision of these guidelines since the first "official" document
was reported on November 4, 1997. The most substantive changes in this most recent
revision are outlined below.
Soft-gel Saquinavir as a First Line Protease Inhibitor
The "soft-gel" formulation of saquinavir (Fortovase) was accepted as a first line protease inhibitor in the preferred regimens for initial therapy. As with ritonavir, indinavir, and nelfinavir, SGC saquinavir should be combined with two nucleoside analogues. The standard dose is 1200 mg tid with meals. "Hard gel" capsule saquinavir (Invirase) is still considered acceptable for use in combination with ritonavir. The dose regimen for this combination is 400 mg of each drug bid (regardless of the form of saquinavir used). HGC saquinavir combined with 2 NRTIs was retained in the "Alternative Therapy" category (although some might question the wisdom of advocating a formulation of saquinavir that is less well absorbed and, gram for gram, twice as expensive). It should be acknowledged that the most extensive data in terms of both numbers of patients and duration of study is with the combination of ritonavir plus Invirase. It also appears that this combination may be better tolerated than ritonavir plus SGC saquinavir. Nevertheless, the improved bioavailability and reduced cost make SGC saquinavir a rational alternative as part of this dual PI combination.
The Role of Ultra-sensitive Viral Load Assays
The threshold of the viral load that defines "no detectable virus" was revisited. The original version of the DHHS Guidelines defined "no detectable virus" as 500 copies/ml based on the threshold of assays for plasma HIV RNA levels in common use at the time of initial discussions in early 1997. The availability of the "third generation" assays for viral load (VL) now provide a threshold of detection of 20-50 copies/ml.
The question posed to the panel concerned the role of these more sensitive assays in determining viral load. Dr. John Mellors, at the 5th Annual Conference on Retroviruses and Opportunistic Infections, reviewed the data from multiple sources with the following conclusion: the nadir of the viral load is the best predictor of long term viral response, and this applies to ultra-sensitive assays as well. Thus, long term viral suppression is more likely in a patient who achieves a nadir of <20 copies/ml as compared to a patient with a nadir of 20-500 copies/ml. Problems are threefold: First, many labs are using assays with a threshold of 400-500 copies/ml, so the lower threshold may not be available to many clinicians. Second, the lower threshold may not be realistic. Most of the large clinical trials with protease inhibitor combinations in treatment naive patients with CD4 counts >200/mm3 show that 75-90% achieve <500 copies at 24-100 weeks, and 60-80% achieve <50 copies/ml. The difference in success between the two assays is usually 10-15% lower. However, patients in HIV clinics are much more heterogeneous compared to clinical trial participants in terms of compliance, prior exposure to antiretroviral drugs, and stage of disease. In "real life clinics," the number who achieve <50 copies/ml is much lower, in some cases as low as 15%. It may not be realistic to make this threshold the standard goal, knowing that most patients may fail, often going on to "spend" most of the therapeutic options early in the course. The third concern is the lack of well-defined clinical correlations with this lower threshold. The assumption is that virologic failure predicts clinical failure, and there is supporting evidence from multiple trials. However, we do not know that this correlation applies to thresholds of <50 copies/ml as well as it does to 500. For these reasons, the Panel concluded that while a lower viral load is clearly preferred, the threshold for "no detectable virus" remains 500 copies/ml.
The Use of d4T in Pregnant Women
The recommendation has been to include ZDV in the antiretroviral regimen of pregnant women, but this may be problematic in patients taking d4T, due to pharmacologic antagonism between ZDV and d4T. It is now recommended that the combination of ZDV plus d4T be avoided in pregnancy. Pregnant women taking d4T should either switch nucleosides or continue the d4T. Intrapartum and postpartum ZDV should be used in all pregnancies according to current guidelines.
Delavirdine Added as Equivalent to Nevirapine as an NNRTI Option *
Delavirdine was added to nevirapine as an acceptable or equivalent NNRTI in the category of "Alternative Options." This decision was based on the 24 week data for Pharmacia Upjohn trial 0021 that tested delavirdine/zidovudine/lamivudine vs. zidovudine/lamivudine.
Saquinavir hgc (Invirase) No Longer "Alternative Option" but becomes "Not Generally Recommended" *
The combination of Invirase plus 2 NRTIs was demoted from the "Alternative Options" category to the "Not Generally Recommended" category. The issue here was the acceptability of the Invirase formulation of saquinavir now that Fortovase is FDA-approved and readily available. (Fortovase shows pharmacokinetic properties that are far superior for half the price of Invirase).
* Due to publication deadline the published guidelines (MMWR 24/04/98) do not include these two revisions.
Source: Adapted from The Hopkins HIV Report (May 1998). Original author: John G. Bartlett, M.D.
The debate on the current utility of ultrasensitive viral load assays is a complex
one. However, given the compelling biological plausibility and initial study results
linking nadir achieved with durability of response, many will be disappointed (but
not surprised) by the panels non-endorsement of this approach. |
5-drug regimen provides improved initial suppression of HIV-1 replication over triple
therapy
Objective
: To compare the viral suppression of two antiviral regimens using 3 drugs and 5 drugs, respectively.Design
: Two open-label studies utilising a 3-drug (zidovudine, lamivudine and ritonavir) and a 5-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug naive patients, except for one in the 5-drug study.Methods
: Participants with 10,000 HIV-1 RNA copies/mL in plasma at baseline were compared by means of Kaplan-Meier curves for time to less than 50 copies/mL, as well as linear regression analysis for the first phase decline using log10 transformed copy numbers.Results
: The elimination rate constants for HIV-1 RNA in 15 participants of the 3-drug study and 9 participants of the 5-drug study were compared. The level of less than 50 copies/mL was reached earlier when using the 5-drug as compared to the 3-drug regimen (p log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first two weeks after the initiation of therapy. When the viral load declines were calculated from day 2 on, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens.Conclusion
: With the 5-drugs used in this study, the median time to reach less than 50 HIV-1 RNA copies/mL was 8 weeks shorter as compared to the 3-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple drug therapy can be improved upon.Ref: Gerrit J. Weverling, Joep M.A. Lange. Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy. AIDS [Fast Track] VOLUME: 12 PAGES: T.B.A.
This study reveals that 3 drug regimens are not optimal, and can be improved upon
in terms of initial suppression of viral load. However, it remains uncertain what
a steeper slope in viral load decay may mean. Does it result in a better immune recovery
or might it be associated with a more durable response? Answers to these questions are
urgently needed to guide therapy. |
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ANTIRETROVIRAL DRUGS
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A review of current knowledge on the new (soft gel) form of saquinavir
Saquinavir is an HIV protease inhibitor which, formulated as a hard-gel capsule (HGC),
was the first drug of its class to become available for the treatment of patients
with HIV infection. Despite the beneficial effects that saquinavir HGC-containing
combination regimens have shown in the treatment of patients with HIV infection, the HGC
formulation has limited oral bioavailability and has shown only modest antiviral
activity in vivo. To overcome this limitation (with the aim of improving antiviral
efficacy), a soft-gel capsule (SGC) formulation of the drug has been developed. At the recommended
dosage of 1200mg 3 times daily, the SGC formulation of saquinavir achieves plasma
concentrations >8 times higher than those in patients receiving saquinavir HGC 600mg 3 times daily. Initial results of trials evaluating the therapeutic efficacy of
saquinavir SGC-containing combination therapy in patients with moderate to advanced
HIV infection are promising. In patients who were previously antiretroviral therapy-naive
or -experienced, short term (less than or equal to 36 weeks) treatment with saquinavir
SGC in combination with greater than or equal to 2 nucleoside reverse transcriptase
inhibitors (NRTIs), or nelfinavir, or 2 NRTIs plus nelfinavir led to marked improvements in virological and immunological markers of HIV disease. In comparative trials,
saquinavir SGC showed improved antiviral activity compared with HGC formulation in
terms of reducing viral load. Furthermore, saquinavir SGC in combination with 2 NRTIs
was as effective as indinavir plus 2 NRTIs in antiretroviral-naive or -experienced patients.
Available data suggest that saquinavir SGC-containing combination therapy may be
of greatest benefit in patients naive to previous antiretroviral therapy. The SGC
formulation of saquinavir appears to be generally well tolerated by adults with HIV infection
Gastrointestinal adverse events, notably diarrhoea, abdominal discomfort, nausea
and dyspepsia, are the most common adverse events occurring during treatment with
the drug. Initial results of several trials that used surrogate markers to assess treatment
efficacy indicate that the SGC formulation of saquinavir, administered in combination
with other antiretroviral drugs, is a effective and well-tolerated treatment for patients with moderate or advanced HIV infection. Although further data are required
before definitive conclusions can be drawn regarding the comparative efficacy and
tolerability of the SGC and HGC formulations, it appears likely that the SGC formulation will replace the conventional formulation as a component of combination regimens
for the treatment of patients with HIV infection.
Ref: Perry, C.M., Noble, S. Saquinavir soft-gel capsule formulation - A review of
its use in patients with HIV infection. Drugs, 55 (3): 461-486 (1998 Mar).
Adefovir Dipivoxil - New Results with Hepatitis B and HIV
On April 6 Gilead Sciences released results of two clinical trials of adefovir dipivoxil
(PreveonTM) for the potential treatment of HIV, and another trial of adefovir dipivoxil at a
lower dose (30 mg) for hepatitis B. The hepatitis trial (which used HIV-negative
volunteers) was clearly a major success, with a reduction of hepatitis B viral load
of 4 logs (99.99%) in the 12-week trial, with adefovir dipivoxil once daily as the only treatment.
The two trials of adefovir dipivoxil for HIV both produced positive results; however,
the sizes of the viral load and CD4 differences were small. It is possible that adefovir
could be more important than the numbers indicate, since it is metabolised differently than nucleoside analogues, and may be effective in cells where those are not.
However, the information released recently does not answer this question, which may
be crucial for determining the role of the drug in HIV clinical practice.
One trial, called GS 411, assigned 85 treatment-naive patients to one of five regimens,
all of which included indinavir (Crixivan):
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indinavir + adefovir + ZDV, or
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indinavir + adefovir + d4T, or
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indinavir + adefovir + 3TC, or
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indinavir + adefovir + ZDV + 3TC, or
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indinavir + ZDV + 3TC. (control)
The other HIV trial, GS 408, randomly assigned 442 volunteers who were already receiving anti-HIV treatment to add either adefovir or a placebo to their existing regimen. At 24 weeks the average viral load drop was -0.39 log in the adefovir group vs. -0.01 logs in the placebo group, a statistically significant difference--about a 0.4 log benefit from adding adefovir in these pre-treated patients.
Adefovir dipivoxil has advantages of once daily administration, and activity against other viruses besides HIV (including hepatitis B, CMV, HHV6, and Epstein-Barr virus). It may also provide a new treatment option for those failing currently available classes of agents.
A central question is whether this drug can contribute to "long-term" control of HIV. Adefovir dipivoxil is active in many cell types, including lymphocytes, monocytes, and macrophages, and it works in both resting and activated T-cells. Even a small viral load drop compared to conventional treatment alone could be important, if this drop is accounted for by viral suppression in a small reservoir of cells not reached effectively by the other treatments, since otherwise these cells would allow HIV replication and therefore development of drug-resistant virus.
Source: AIDS TREATMENT NEWS Issue No. 293, April 17, 1998
Author: John S. James
The concern with nucleotides (as opposed to nucleoSIDES) is the possibility of renal
dysfunction over prolonged dosing. This is a well-known adverse event with cidofovir
(a nucleotide analogue) and may be an issue with adefovir. Studies beyond 20 weeks
are urgently needed to address this concern. The results of GS411 should be regarded
with caution due to the small numbers (n=17) per arm and the short duration, preventing
a valid conclusion. It remains to be seen how much impact adefovir really has. Additionally, no studies have been reported in pre-treated patients, hence a role in salvage
is unclear. Anti-CMV activity may lead to consideration as an OI prophylaxis in late
stage patients. Gilead have not allowed for any compassionate access to this drug
in Europe despite recent announcements of an expansion of the access programme in the
US. |
Nevirapine and Rashes
Andreas Barner and Maureen Myers from Boehringer Ingelheim Pharmaceuticals respond
in a letter to the Lancet to a recent report linking use of the anti-HIV drug nevirapine
with Stevens-Johnson syndrome. The authors note that the instructions for the medication include warnings about rash development, along with instructions for rash management.
They note that a lead-in dose should be used to reduce the risk of rash and that
patients developing severe rashes should discontinue use and not be rechallenged.
One study found that 35 percent of 350 nevirapine-treated patients developed a rash
of any severity, as compared to 19 percent of 308 controls. A study conducted by
Boehringer Ingelheim of 2,800 nevirapine recipients indicated a 0.3 percent incidence
of Stevens-Johnson syndrome or toxic epidermal necrolysis. The authors note that "given
the major challenges facing HIV-1-infected individuals, it would be unfortunate to
limit treatment options unduly for patients because inadequate information was available upon which to make a treatment decision."
Ref: Barner, Andreas; Myers, Maureen. Lancet (01/04/98) Vol. 351, No. 9109, P. 1133;
For original report see Doctor Fax issue 43. |
Lamivudine-Induced Paronychia
Researchers from Italy's Ospedale Maggiore di Milano report 12 cases of paronychia in HIV-1 infected patients receiving lamivudine. Eleven of the patients were men, none had diabetes and only one had a previous history of paronychia. All of the patients had been on lamivudine regimens for approximately three months and had not received any other medications during that time. The patients were treated with topical antiseptics; two also received oral macrolides, and four had surgery for the infection. Five patients healed in one months with no recurrence, while the other six had relapses. The authors note that paronychia is normally caused by candida in HIV-1 patients and is rarely seen in patients with CD4 cell counts below 200 cells per microlitre. The mean CD4 cell count among the 12 patients was 350 cells per microlitre with a range of 44 cells to 450 cells.
Ref: Lancet Zerboni, Roberto; Angius, Anna Grazia; Cusini, Marco; et al. (25/04/98) Vol. 351, No. 9111, P. 1256;
As a component of NRTI regimens only, 3TC has never been reported to induce paronychia.
However, there have been increasing reports of paronychia associated with PI use
(primarily indinavir). This report may represent a case cluster rather than a cause-effect of 3TC. |
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OPPORTUNISTIC ILLNESS
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Protease Inhibitors Prolong Survival in AIDS Patients with CMV Retinitis
Dr. John C. Walsh of Chelsea and Westminster Hospital in London and colleagues report
in the April 16th issue of AIDS that antiretroviral therapy including a protease
inhibitor significantly increases survival in AIDS patients with cytomegalovirus
retinitis. While protease inhibitors have been credited with decreasing mortality rates among
the AIDS population, it is unclear whether immune system damage would be fully reversible.
Patients with severe chronic immunodeficiency, such as those with CMV retinitis, could be expected to derive the least benefit from the therapy, but the new study
shows a dramatic increase in survival time. According to the authors, who studied
147 patients with AIDS-related CMV retinitis, median survival time prior to the introduction of protease inhibitors was 256 days, while the median survival time increased
to 720 days after the drugs introduction.
Abstract:
Objective
: To assess the effect of combination antiretroviral therapy including HIV protease inhibitors on the survival of patients with cytomegalovirus retinitis (CMVR).Design and participants
: A longitudinal study of patients with CMVR diagnosed between October 1992 and May 1996 and followed to May 1997.Setting
: UK National Health Service specialist HIV medicine department.Outcome measure
: Time to death from first diagnosis of CMVR. Data were censored on 31 May 1997.Results
: Data were available on 147 patients with CMVR. Median survival of CMVR patients before December 1995 was 256 days [95% confidence interval (Cl), 197-315]. Following the introduction of protease inhibitors in December 1995 this rose to 555 days (95% Cl, 351-759). By 31 May 1996 median survival for the entire group of patients alive with CMVR had risen to 720 days (95% Cl, 551-889). The mean survival after CMVR diagnosis was 224 days (n = 89; 95% Cl, 186-261; 1-year survival, 16%) in those who took no further antiretroviral therapy, 353 days in those who took nucleoside reverse transcriptase inhibitors but no protease inhibitors (n = 34; 95% Cl, 289-418; 1-year survival, 50%), and 914 days in those who took a protease inhibitor (n = 24; 95% Cl, 768-1059; 1-year survival, 83%; P < 0.0001). Multivariate analysis showed that the strongest independent predictor of improved survival was having ever received a protease inhibitor after CMVR (relative risk of death, 0.063; 95% Cl, 0.027-0.149; P <0. 0001).Conclusions
: The use of HIV protease inhibitors in combination antiretroviral therapy has been associated with a marked increase in the survival of patients with CMVR.Ref: Walsh, J.C., Jones, C.D., Barnes, E.A., Gazzard, B.G., Mitchell, S.M. Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors. AIDS, 12 (6):613-618 (1998).
Source: CDC Daily News Update
The reported median survival of 720 days for PI recipients is 720 days and increasing,
i.e. many of these patients are still alive to date. These data encourage the view
that CMV patients do gain significant benefit from PI containing combinations. The
question of stopping anti-CMV maintenance therapy is now being addressed. |
Progression Of CMV Retinitis May Indicate Inadequate Ganciclovir Maintenance
Ganciclovir protocols commonly used for patients with cytomegalovirus (CMV) retinitis
may be inadequate, according to British researchers.
Dr. E. Frances Bowen, of the Royal Free Hospital and School of Medicine in London,
UK, and others performed serial ophthalmoscopy and polymerase chain reaction studies
for a median of 7 months in 45 patients whom they had treated for first episodes
of cytomegalovirus retinitis.
They explain, in the April 16th issue of AIDS, that they wanted to determine whether
or not recurrence of viraemia during ganciclovir maintenance therapy for CMV retinitis
correlates with development of CMV disease at a new site,
progression of the retinal disease, or acquisition of genetic changes associated with
ganciclovir resistance. Dr. Bowen and colleagues used PCR samples to determine CMV
viral load and genetic markers of ganciclovir resistance.
According to their report, viraemia, documented by polymerase chain reaction, "...correlated
strongly with the development of new episodes of CMV disease." The authors add that
"...the minority who were [CMV PCR]-positive...may have reinfected (reseeded?) their eye, and frequently had markers of ganciclovir resistance."
"These results have...practical implications, "Dr.
Bowen's team says. "[Patients] who have progression of retinitis while remaining [CMV
PCR]-negative may have inadequate intraocular levels of [ganciclovir] and should
be considered for intravitreal therapy.... Those who have progression of retinitis
and are [CMV PCR]-positive should be treated systemically with an alternative drug at induction
doses. Meanwhile, CMV DNA extracted from blood should be examined for evidence of
[ganciclovir] resistance to inform decisions about the management of future cases
of retinitis progression."
Ref: AIDS 1998;12:605-611.
Source: CDC Daily News Update
Ganciclovir implants and intraocular injections are now widely used in anti-CMV maintenance
therapy to guard against the risk of inadequate intraocular drug levels from IV or
oral administration. In some centres implants are used first line. Patients should be aware of the risk of retinal detachment and the fact that this risk is variable
depending on the experience of the physician performing the implant. Additionally
CMV PCR is not universally available and the threshold indicating progression from
latent to reactivated disease is not well defined. |
Intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis
Abstract :
To assess the effect of intravenous cidofovir on delaying progression of previously
treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomised, controlled
comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite
treatment with ganciclovir, foscarnet, or both were randomised to receive induction
cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either
5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration
were administered with each cidofovir dose. Retinitis progression was assessed in
the first 100 patients by bilateral, full-field retinal photographs read at a central
reading centre by an ophthalmologist masked to treatment assignment. Incidence of
side effects, changes in visual acuity, and mortality were also assessed. Median
time to retinitis progression as assessed by retinal photography was not reached
(95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was
49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic
proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including
constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir
therapy is effective in delaying progression of CMV retinitis that had previously
progressed using other anti-CMV therapies.
Ref: , Lalezari,J.P., Holland,G.N., Kramer,F. et al. Randomised, controlled study
of the safety and efficacy of intravenous cidofovir for the treatment of relapsing
cytomegalovirus retinitis in patients with AIDS J.Acquir.Immune Defic.Syndr.Hum.Retrovirol.,17 (4):339-344 (1998 Apr 1)
Cidofovir and the other iv. anti-CMV drugs are an option for patients with CMV end
organ disease and no immunological improvement despite maximal antiretroviral therapy.
The iv. regimens providing systemic CMV suppression. However, implants have a more
direct effect on the retinitis itself. Because of concerns over irreversible renal toxicity
and cross-resistance to ganciclovir and foscarnet, cidofovir is generally "saved"
until last (i.e. patients who have failed on ganciclovir +/- foscarnet with bilateral CMV retinitis. Maximal antiretroviral therapy should also be maintained to induce
immunological improvements. Despite the need for careful monitoring to avoid renal
toxicity, cidofovir has the potential to offer patients vastly improved quality of
life compared to the daily i.v. infusions needed with foscarnet or ganciclovir. Cidofovir
is administered i.v. over one day every 2-3 weeks. |
Failure of Cytarabine in Progressive Multifocal Leukoencephalopathy
Researchers with the AIDS Clinical Trials Group 243 Team studied 57 patients with
HIV and progressive multifocal leukoencephalopathy and found that cytarabine treatment
in conjunction with antiretroviral therapy does not improve patient prognosis. Additionally, high doses of antiretroviral treatment alone did not result in improved patient
survival as compared to untreated patients. The researchers divided the patients
into three subject groups: those receiving only antiretroviral agents, those receiving
antiretroviral agents in conjunction with intravenous cytarabine, and those receiving
antiretroviral agents and intrathecal cytarabine. All medication was administered
for 24 weeks. Fourteen patients in each group died and only seven patients completed
the therapy. The researchers note that the study was conducted before the advent of highly
active antiretroviral therapy, which has been reported to be useful in the treatment
of multifocal leukoencephalopathy.
Ref: Hall, Colin D.; Dafni, Urania; Simpson, David; et al. New England Journal of
Medicine (05/07/98) Vol. 338, No. 19, P. 1345.
Source: CDC Daily News Update
These results would appear to end the use of cytarabine in PML. Case reports have
indicated that cidofovir may be beneficial and further studies are exploring this
possibility. The management of PML includes confirming diagnosis and treating HIV-infection
as aggressively as possible. PI containing regimens have been reported to reverse
PML symptoms and prolong life expectancy. |
Intracranial Tuberculoma may be Exacerbated by HAART
UK researchers describe what they believe is first documented case of expansion of
intracranial tuberculomas following the induction of highly active antiretroviral
therapy (HAART) in an HIV-positive patient. They suggest that this paradoxical phenomenon
may be linked with immune system reconstitution resulting from HAART.
Dr. John A. Crump and colleagues at the Royal Free Hospital in London report the case
of a 35-year-old man in the April issue of Clinical Infectious Diseases
. The patient, who first tested positive for HIV in September 1996, began HAART in
December of that year. Despite a decrease in viral load, the patient experienced
lethargy, sweats, and weight loss 5 weeks later. Palpable lymph nodes were found
on physical examination, and the patient was ultimately diagnosed with tuberculosis.
"Five months after starting antituberculous therapy, the patient had a grand mal seizure,"
Dr. Crump, who is currently at Christchurch Hospital in New Zealand, and colleagues
report. Results of MRI "...showed enhancing lesions with surrounding vasogenic edema, compatible with tuberculoma." After tuberculoma was confirmed, the patient began
a course of oral prednisolone while continuing therapy and the intracranial lesions
abated.
Dr. Crump's team suggests that "...immune reconstitution may have contributed to the
paradoxical expansion in this case, particularly as this paradoxical expansion is
reported so rarely in association with HIV infection. They therefore recommend that
clinicians be alert for neurological symptoms in HIV-positive patients with miliary tuberculosis
who are also receiving HAART.
Ref: Clin Infect Dis
1998; 26: 1008-1009.
Source: CDC Daily News Update
An increase in inflammatory reactions to MAC, other OI's and skin conditions has also
been reported in immunological responders to combination antiretroviral therapy. |
Weight Loss Directly Related to Plasma HIV Load
Dr. Fred R. Sattler and researchers at the University of California School of Medicine
in Los Angeles report that plasma HIV load is directly proportional to weight loss
in HIV-infected patients with wasting. The study, published in the April 15th issue
of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, showed
that 32 of 33 patients experienced continuous weight loss as their HIV RNA levels
increased. The HIV-infected patients evaluated had lost approximately 10.5 kg over
a period of 461 days. The subjects' median viral load was 46,887 copies/ml. In reviewing
their data, the researchers found that as viral load levels increased, so did the
degree of weight change observed in the study subjects.
The loss in weight was described as "chronic" and "relentless" in 32 of 33 subjects,
nearly half of whom showed no evidence of opportunistic infections or digestive complications
that might explain their weight loss. As well, factors such as low testosterone levels and changes in body cell mass were ruled out as the cause of weight loss
and viral load increases in these subjects. Instead, the subjects' dramatic weight
loss was attributed to the increased activity of proinflammatory cytokines which
accompanies HIV replication. Not surprisingly, the researchers conclude that "...aggressive
treatment of the primary infection should be the first pharmalogic intervention for
treatment of wasting if RNA levels are elevated."
Source: CDC Daily News Update
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PATHOGENESIS
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Dendritic Cells Express Multiple Chemokine Receptors Used as Coreceptors for HIV Entry
Dendritic cells appear to have multiple chemokine receptors that act as HIV entry
coreceptors, according to researchers from the Laboratory of Immunoregulation and
the Laboratory of Host Defenses at the National Institute of Allergy and Infectious
Diseases. The scientists found that CCR5 was used by the cells for entry of macrophage-tropic
isolates, while CCR3 may also be used as an entry coreceptor by certain dual-tropic
strains. The team also found that SDF-1 induced a calcium flux, which could allow
dendritic cells to be infected by T cell line-tropic HIV, despite the fact that CXCR4
was not expressed on the dendritic cells. The researchers note that this may provide
evidence for the existence of a dendritic cell non-CXCR4 SDF-1 receptor used by T-tropic HIV strains. Additionally, dendritic cells from patients homozygous for a 32-base-pair
deletion of the CCR5 allele can be infected with M-tropic HIV. The researchers suggest
that new methods of disrupting HIV initiation and propagation may come through the delineation of the coreceptor usage spectrum on dendritic cells.
Ref: Rubbert, Andrea; Combadiere, Christophe; Ostrowski, Mario; et al. Journal of
Immunology Online (15/04/98) Vol. 160, No. 8, P. 3933.
High-Intensity Exercise Does Not Increase HIV Load
Exercise training appears to be a safe way to build muscle mass in people with HIV
infection, according to a report presented at the Experimental Biology '98 Meeting
in San Francisco, California.
Regular physical activity has long been viewed as an effective way of managing stress
and contributing to an improved quality of life for people with HIV. As well, resistance
training in particular is known to help increase lean body mass, or muscle, which helps the body fight off disease and prevent muscle wasting. In general, however,
people with HIV have traditionally been advised to exercise moderately for fear that
intense activity might actually weaken the immune system and possibly increase viral
load. However, researchers at Tufts University in Massachusetts have recently released
evidence to the contrary.
Dr. Ronenn Roubenoff and colleagues studied the effects of intensive exercise on 25
HIV+ subjects. Viral load measures taken immediately after 15 minutes of high-intensity
exercise and again one week later showed no increase in HIV activity. In fact, a
slight decrease in viral load was observed.
Given the risks associated with pharmaceutical methods of battling wasting in people
with HIV, such as testosterone and growth hormone injections, Dr. Roubenoff concludes
that exercise is a safe alternative for building vital muscle mass in people living
with HIV.
Source: CDC Daily News Update