| ANTIVIRALS |
Reports of new research published in the August issues of Nature Medicine and Nature Structural Biology raise questions for people with HIV disease who are considering their treatment options.
New data explains why the reverse transcriptase inhibitor AZT has limited efficacy in suppressing HIV-1 replication.
Before AZT can block viral replication by preventing RNA transcription, the drug must be activated by phosphorylation to the triphosphate form, Dr. Roger S. Goody and colleagues from the Max Planck Institute in Dortmund explain. In their Nature Medicine paper, the researchers report that phosphorylation to the intermediate monophosphate form is uncomplicated, but this provides a poor substrate for the interaction with thymidylate kinase to produce the triphosphate. The net result is a low level of active AZT triphosphate and accumulations of toxic AZT monophosphate.
The two reports represent some "remarkable detective work," according to Dr. George L. Kenyon of the University of California in San Francisco. By using "...enzyme kinetic studies in conjunction with X-ray crystallography in a complementary fashion to implicate an induced movement in the conversion enzyme, thymidylate kinase," they have identified the most likely "...'bottleneck' or limiting step in AZT's activation."
"The inability to achieve a highly effective concentration of AZT [triphosphate] within the cell sufficient to suppress HIV replication invariably leads to resistance selection," add Drs. Daria Hazuda and Lawrence Kuo of Merck Research Laboratories in West Point, Pennsylvania.
ZDV has a number of drawbacks already identified with its use including:
All nucleoside analogues have drawbacks in terms of toxicity and probably in terms
of accumulating cellular resistance overtime. However, a second thymidine analogue
reverse transcriptase inhibitor is licensed in Europe for use in HIV-infected adults
- d4T (stavudine) which does not have the above described limiting step in its phosphorylation.
This drug has been shown to have equivalent CNS penetration to ZDV and a favourable
tolerance and resistance profile. In combination with ddI it has been shown to produce falls in viral load with a durability which is impressive for a double nucleoside
analogue combination (see ATP DocFax Issue 16). Studies are also ongoing of d4T with
ddI, ddC or 3TC in combination with a variety of protease inhibitors. |
Highly active antiretroviral therapy can greatly reduce lymph-node HIV levels, but
even a short interruption means starting all over again. This sobering finding shows
that there are strict limits to even the most effective currently available anti-HIV
regimens. HIV infection of the lymph nodes is often spoken of as the central lesion of
HIV disease. With the advent of potent combination therapies hopes were raised that
HIV might be eliminated or permanently suppressed both in the blood and in the lymphatic tissues.
The good news, announced Joseph K. Wong of the University of California, San Diego,
is that HIV in lymphoid tissues is reduced by 4 log10 in patients whose plasma viral
loads remain undetectable after a year of therapy. The bad news is that lymph-node
HIV levels remain high in patients with relatively low-level plasma viraemia. Perhaps
even more disappointing is the finding that lymph-node virus levels rebound back
to pre-treatment levels during brief interruptions of therapy.
"Even modest plasma viraemia during therapy can be associated with very significant
virus loads in lymphoid tissues," Wong said. "Even temporary interruptions [of therapy]
appear to allow for repopulation of lymphoid tissues and the resetting of the clock
for the decay of lymph-node virus."
Wong announced the findings in a presentation to "New Opportunities for HIV Therapy
- From Discovery to Clinical Proof-of-Concept," the 2nd Joint Conference of the National
Institute of Allergy and Infectious Diseases (NIAID) Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) and the National Cooperative Drug Discovery
Groups for the Treatment of HIV Infection (NCDDG-HIV), held June 22-26, 1997, in
Vienna, Virginia.
Wong and colleagues evaluated HIV RNA and DNA levels and determined resistance mutations
in blood and inguinal lymph-node biopsies from patients enrolled in the Merck 035
study comparing indinavir plus zidovudine (AZT) plus lamivudine (3TC) to indinavir
alone and to AZT plus 3TC. Nine of the patients examined by Wong et al. received the
triple-drug therapy; they had relatively advanced disease with baseline CD4 counts
ranging from 69 to 274 cells/(micro)L and a median plasma virus load of 41,100 copies/ml.
All had previously received nucleoside therapy, but all were naive for indinavir and
3TC.
"After one year of therapy, viral RNA levels in the lymphoid tissues of individuals
receiving triple-drug therapy who had undetectable plasma RNA levels were reduced
by 4 log[10] but were still detectable," Wong et al. wrote in their presentation
abstract. "However, in subjects on the triple- drug regimen with interruption of therapy or
in those treated with AZT/3TC alone, lymphoid viral loads were 10(7) to 10(9) copies
of HIV RNA/g of tissue: levels indistinguishable from those expected for untreated
patients."
In patients with "suboptimal" response to triple-drug therapy (i.e., measurable plasma
virus load), replication- competent virus could be recovered from both blood and
lymphoid tissue. And this virus apparently acquires resistance to the treatment medications. "Virus in subjects with inadequate suppression accumulate drug-resistance mutations
indicating high levels of virus replication," Wong said. When patients interrupted
therapy due to adverse reactions or failure to comply with strict dosage requirements, the virus quickly rebounded in lymphoid tissue.
Source: Aegis.
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This data raise further pessimism regarding the likelihood of successful eradication
protocols using current triple therapy regimens. Additionally, the presence of continued
viral replication in the presence of drug suggests resistance will inevitably develop. Physicians must therefore consider what therapies will be available to their
patients as second-line combinations after failure of initial regimens, including
those patients who achieve an initial optimal virological response. More data becoming available also strongly suggests that early failure (ie. before multiple and compensatory mutations accumulate), if detected and acted upon, may enhance the likelihood of continued viral suppression on change of agents. The importance of adherence and choosing a regimen individualised to the patients needs and capabilities is also underlined by this study. Drug holidays for toxicity or non-adherence may represent a set back for patients in terms of gaining long term (eg immune-restoration) benefits from therapy. |
Numerous published articles and the development of a new soft-gel capsule formulation
of saquinavir by Hoffmann-La Roche raise important issues for people with HIV who
are currently taking or considering taking saquinavir (Invirase).
The Scientific Advisory Committee of the San Francisco AIDS Foundation has prepared
a summary of information regarding saquinavir formulations and dosing which it has
published in its quarterly publication BETA. This information is available on the
internet at: http://www.sfaf.org/b33advoc.html
This latest article adds to concerns amongst doctors and patients regarding the antiviral
potency of the currently available formula of saquinavir when prescribed at the recommended
dose (600mg tid). These concerns culminated in the exclusion of saquinavir from the list of recommended protease inhibitors to include in a first-line triple
combination in the recently issued new US DHHS guidelines for antiretroviral therapy
(see ATPs Doctor Fax Issue 26).
Ref: Annals of Internal Medicine 15 July 1997. 127:119-125.
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Interestingly the study authors comment that... Five patients had another previously
unreported syndrome that consisted primarily of dysuria and urgency with crystalluria.
We believe that these symptoms are caused by dense crystalluria that irritates the
mucosa of the bladder and urethra. This entity can easily be misdiagnosed as acute
infectious urethritis and thus can lead to the unnecessary use of antibiotics. With regard to management this study reveals that asymptomatic crystalluria was present in 20% of patients receiving indinavir. The appearance of crystalluria was not predictive of the subsequent development of symptoms and is therefore not an indication for withdrawal of indinavir. On the other hand, the presence of crystalluria is confirmatory that the symptoms are probably due to indinavir and suggests the need for increased fluid intake and possibly temporary drug withdrawal. In conclusion the authors state that of the four currently approved protease inhibitors, indinavir has been the most widely used because of its efficacy, its favourable pharmacologic properties, its tolerability, and the relatively few drug-drug interactions associated with it. These findings do not substantially alter this profile. Symptoms, when they develop, can usually be treated conservatively with hydration and drug withdrawal, and many patients restart indinavir therapy. Nonetheless, it is important that physicians who treat HIV-infected patients with indinavir be aware of the possible spectrum of urologic complications. When symptoms do occur, this information should allow formulation of a narrowed differential diagnosis and development of an appropriate therapeutic plan. |
| CURRENT OPINIONS |
Data from multiple small mostly non-randomised studies examining use of a second protease
inhibitor (PI) after failure on the first choice PI were presented at the recent
drug resistance workshop in Florida.
In 16 patients switching after a mean 11 months SQV to NFV (some of whom also switched
NAs), 11 achieved VL reductions of >O.5 log (3 patients to <400 copies/ml) but only
2 patients remained undetectable to week 16. Subsequent switch to indinavir plus
nevirapine (continuing NAS) resulted in a mean VL reduction at week 8 of 1.58 log; with
6/10 patients achieving <400 (abstract 64). Similarly 10 patients completing >24
weeks SQV at high dose (3600 or 7200 mg/day) switched to IDV (monotherapy for 4 weeks
then with ZDV/3TC) achieved a mean week 4 VL reduction of 1 21log increasing to 1.94log
at week 24 (after addition of NAS). These responses were despite presence of multiple
resistance associated mutations including at L9OM and G48V (abstract 87). Twelve
patients with a median 4.9 years
SQV exposure adding RTV (500mg BD) achieved transient VL, reductions (1.52, 0.97
and 0.03 at weeks 2, 4, and 16). Patients with no baseline SQV mutations achieved
greater and more sustained responses (2log at week 16) (abstract 84). Thus there
may be an association with duration of failure and chance of responding to a second agent.
Anyone with detectable virus on SQV, or indeed any PI, should consider immediate therapy
modification to limit the chance of selection of cross-resistant virus.
With nelfinavir (NFV) (abstract 18) in vitro cross-resistance appears rare in the
presence of the typical codon D3ON mutation (based on 6 clinical isolates) with isolates
obtained from 170 NFV treated patients (up to 52 weeks) not having mutations at codons 48, 82, 84 and only rarely 90. Isolates from persons failed on one of the 3 other
PIs showed 59% retained sensitivity to NFV. However, data presented found that in
64 patients with 1 prior PI 61% did not achieve a >0.5log reduction on switching
to nelfinavir.
In 19 patients with a mean 5.2 months prior indinavir or ritonavir use experienced
a mean 1.6log reduction in VL at one month when treated with combination therapy
including the SQV-RTV double PI combination. Unfortunately, responses had returned
to baseline by month 2 suggesting the benefits of this highly active combination may be limited
by prior therapy with some PIs (abstract 76). Similarly, of twenty indinavir failures
switched to SQV/RTV (plus other agents in some cases) only 6 patients (35%) achieved a 1log VL drop at week 4. Failure of response was associated with extensive cross-resistance
selected for by indinavir therapy (abstract 81). This suggests a lower rate of responses
to second line therapy following indinavir, consistent with in vitro resistance data.
Ultimately, cross-resistance appears possible with all PIs. Initial therapy with a
PI should not involve a compromise in terms of activity but should involve close
monitoring of VL to prompt immediate therapy modification upon either an inadequate
response or return to detectable virus.
Author: Graeme Moyle.
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It is becoming increasingly clear that inadequate response or virological failure
whilst receiving a protease inhibitor containing regimen is highly undesirable both
in terms of current health status and foreclosure of options for future treatment. Genotypic and phenotypic testing is still only available as a research tool with results difficult to interpret. The question that must, therefore, be urgently addressed is how are clinicians to detect the emergence of resistance in a timely fashion in patients currently receiving protease inhibitors? It is widely accepted that continued viral replication (ie. detectable viral load) whilst on treatment is the driving force for genetic resistance to antiretroviral drugs. It is also clear that even though viral load may be below the level of detection of current assays, viral evolution is still ongoing. It is biologically plausible, with evidence from studies now emerging, that the lower the viral load (even when below detectable) the slower the emergence of resistance and the longer the durability of action of currently available antiretroviral agents. It therefore follows that close and frequent monitoring of plasma viral load for patients receiving antiretrovirals (particularly protease inhibitors) is essential to early detection of resistance and prediction of therapeutic failure. HIV emerging after early escape from drug pressure is likely to be attenuated, have perhaps 1 mutation and limited cross-resistance. If therapy is not modified quickly at this stage accessory mutations will accumulate, viral fitness will recover and cross-resistance is likely to be wide. Both physician and patient will then find themselves in an unenviable position. A viral load monitoring programme to detect early failure in an attempt to prevent cross-resistance would require;
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This schedule would ensure that emergent virus has no more than 4-8 weeks in which
to consolidate its resistance and cross-resistance. |
| PATHOGENESIS |
Using stringent criteria based on all known predictors of disease progression, French researchers believe that very few HIV-positive individuals are true long-term nonprogressors (LTNPs). In a study, which is published in the 1st August issue of Blood, they found that the majority of individuals termed as LTNPs "...present biological signs of HIV disease progression."
Even Individuals Considered as Long-Term Nonprogressors Show Biological Signs of Progression
After 10 Years of Human Immunodeficiency Virus Infection.
Despite a decade of human immunodeficiency virus (HIV) seropositivity, a few individuals
termed as long-term nonprogressors (LTNPs) maintain a stable CD4+ T-cell count for
a period of time. The aim of this study was to establish, through the sequential
determination of all known predictors of HIV disease, the proportion of such patients
having stringent criteria of true long-term nonprogression. Among 249 individuals
who were HIV-infected and prospectively followed up over a 10-year period (1985 to
1995), 12 having a CD4+ T-cell count greater than 500/mL (LTNP I group) and 9 having a CD4+
T-cell count less than 500 but stable over time (LTNP II group) after at least 10
years of infection without intervention of antiviral therapy, were studied over the
entire follow-up period. The plasma HIV RNA copy number and the serum concentrations of
p24 antigen, each anti-HIV antibody, neopterin, beta-2-microglobulin, Immunoglobulin
(Ig) G and IgA were determined every 18 months over the study period. Cellular and
plasma viraemias were cross-sectionaly assayed in all 21 patients. Only two patients had
strictly no marker of progression over the follow-up period. They were the only ones
who had, over the 10-year period, a viral copy number too low to be detected. The
other patients had a viral copy number higher than 400/mL at at least one visit and increasing
over the follow-up period, and they evidenced one or more markers of virological
or immunological deterioration. Cellular viraemia was positive in all patients but
two, while plasma viraemia was negative in all but one. The population of individuals
termed as LTNPs is not virologically and immunologically homogeneous. The majority
present biological signs of HIV disease progression. A new pattern of true LTNP can
be drawn through stringent criteria based on the whole known predictors. This pattern appears
to be rare in HIV-positive population.
Ref: Blood 1997;90:1133-1140.
| Whilst the majority of persons infected with HIV will progress at some point, it remains to be determined when treatment should start. Whilst it is biologically plausible to start early with therapy many of the slow progressors may experience drug related toxicity prior to when risk of symptoms would have begun. Slow progressors, who have not become immunodeficient after 10 to 15 years of follow-up may continue to have detectable viral load. Consideration of the duration of treatment and impact of treatment on quality of life should be made prior to starting treatment in LTNPs with detectable viral load. |
New research published in the journal Nature suggests that HIV invades human cells
on several fronts and that future AIDS treatment must be designed to block multiple
pathways. Researchers from New York University Medical Center found that human immune
system cells have two previously undiscovered receptors that HIV can latch onto to penetrate
the cells.
To infect a cell, the human and simian immunodeficiency viruses have to attach to
its membrane, then enter the cell, before subverting the genetic machinery to their
own ends. The CD4 membrane receptor has long been known to be essential, but not
sufficient, for this process. Eighteen months ago, the first so-called co-receptor was discovered.
More have since been identified, and the latest tally for HIV-1 is six. The possibilities
thereby opened up for developing drugs that compete with the virus for these binding sites is counterbalanced by the prospect of viral evolution to use alternative
co-receptors.
Ref: Nature 388, 230-231 (1997)
Nature 388, 296 (1997)
| These data suggest CCR5 or CXCR4 blockers, currently in concept or phase 0 development are unlikely to work in vivo as HIV has multiple pathways to enter cells. |
OPPORTUNISTIC ILLNES |
New research indicates that for initial treatment of AIDS-related cryptococcal meningitis,
the use of higher-dose amphotericin B and flucytosine is associated with a greater
rate of cerebrospinal fluid sterilisation and lower mortality than other drugs. Researchers for the National Institute of Allergy and Infectious Diseases Mycoses Study
Group and the AIDS Clinical Trials Group studied more than 300 patients who were
experiencing their first episode of AIDS-related cryptococcal meningitis. After two
weeks, 60 percent of those patients receiving amphotericin B plus flucytosine and 51 percent
of the amphotericin-only group had negative cerebrospinal fluid cultures. During
the second phase, researchers administered itraconoazole or fluconazole for eight
weeks. Some 72 percent of those receiving fluconazole and 60 percent of those receiving
itraconazole had negative cultures after 10 weeks. Moreover, the proportion of patients
who had clinical responses was similar with the two drugs. A multivariate analysis
found that the addition of flucytosine during the first phase and treatment with fluconazole
during the second phase was independently associated with cerebrospinal fluid sterilisation.
The researchers also noted that itraconazole can be substituted for patients unable to take fluconazole.
Ref: New England Journal of Medicine (07/03/97) Vol. 337, No. 1, P.15
Source: AIDS Daily Summaries
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Amphotericin with or without flucytosine (depending on clinic) is the standard of
care for patients with moderate or severe cryptococcal meningitis. These data suggest
inclusion of flucytosine should become the standard of care. In mild meningitis oral
fluconazole may be used.
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At the National (US) Lesbian and Gay Health Conference in Atlanta, researcher Joel
Palefsky warned of the increased risk of anal cancer faced by people living with
HIV, predicting that the incidence of this type of cancer is likely to rise over
the next five years.
According to Doctor Palefsky, men and women who engage in anal intercourse run the
greatest risk of contracting a strain of HPV (Human Papilloma Virus) that can lead
to cancer. Among those living with HIV, the risk is greater still, particularly as
their immune system weakens over time.
Among 600 subjects of a study conducted at the University of California in San Francisco,
75% of men with severe immune suppression had pre-cancerous anal dysplasia at the
start of the study, compared to 20% among HIV- men. Four years later, the condition
of twice as many immunosuppressed men had worsened compared to the HIV- subjects.
Furthermore, a second study revealed that antiviral treatment that had led to an
increase in CD4+ numbers had no effect on the abnormal cells observed.
In light of these findings, and given that anal cancer usually takes several years
to develop, Dr. Palefsky has suggested that the number of cases of anal cancer will
rise sharply in coming years as new treatments offer hope of a longer life to many
patients. To help counter this potential threat, Dr. Michael Berry of UCSF recommends regular
anal Pap smears and colposcopic examinations for all gay and bisexual men living
with HIV, as well as HIV- negative men and women who have engaged in anal intercourse.
As treatment, Dr. Berry recommends the surgical removal of lesions by fulguration
or electrotherapy.
Source: CATIE-News
| An increased incidence of anal cancer has been previously reported in HIV infected men (together with a range of other malignancies). Colposcopy or smears have not been recommended or widely used in the UK as a low proportion of dysplastic lesions subsequently progressed to cancer (compared to cervical lesions in women, particularly HIV-infected) and physicians were uncertain how to treat - laser therapy or electrotherapy may need to be extensive, cause both short and long term anal problems and may not cure lesions. This study suggests a role for piloting anal colposcopy to assess its value in prevention of anal cancer amongst individuals at highest risk. |
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TJ-48 is also known as minor bupleurum combination, sho-saiko-to and xiao chaihu tang.
It is a combination of seven chinese herbs in strict ratio (bupleurum, scutellaria,
ginseng, pinellia tuber, licorice, ginger and jujube dates). It has also been shown
to have immunomodulating and antiretroviral activity in vitro. Evening primrose and flaxseed oil supplements are readily available at chemists. |