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STANDARDS OF CARE
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The following Framework document for antiretroviral therapy has been adopted and approved by the steering committee of PACT (National Association of Providers of AIDS Care and Treatment) following discussions with ILHHCG (Inner London HIV Health Commissioners Group). Following consultation it has been accepted by the Inner London Health Authorities. The primary intention is to set out some durable principles on the use of antiretroviral therapy in HIV infected adults in order to inform the contracting process. It is an indication of the principles of contemporary clinical practice, based on evidence in the published literature and as presented at recent scientific meetings. It is not comprehensive, nor is it a detailed professional guide to current practice, which will be provided by other groups (by, for example, BHIVA in the UK and US-IAS in the USA), as well as within individual centres. Such guidelines are designed for other purposes and will necessarily need regular updating. However, this framework is compatible with existing guidelines and represents a substantial consensus; It may thus provide a useful summary and starting point for clinical colleagues and patients.
It is evident that, for the present purpose, it is not possible or helpful for the Framework to specify particular drugs for combination therapy, since these will be determined by factors particular to individual patients and will be constantly changed by new information as it becomes available. The use of individual antiretroviral drugs in practice can be assessed through the existing monitoring scheme.
The Framework covers the setting of chronic established adult HIV infection, which represents the vast majority of prescribing of antiretroviral drugs. Paediatric HIV infection is a small and highly specialised area; advice should be sought from specialist units for current practice. This document does not deal specifically with the setting of acute seroconversion, nor the drugs to be used following needlestick injury: Some early studies indicate that there may indeed be a role for combination antiretroviral therapy in patients with acute seroconversion, but the drugs to be used, the patients to be treated, the treatment duration and protocols for latter therapy have yet to be resolved. there is evidence to support the use of antiretroviral therapy following significant inoculation injury, but the optimal regime and timing are as yet unclear; others are producing guidance on this (CDC in USA and EAGA in UK).
The Framework assumes that patients are attending for regular clinical follow-up under
the supervision of a physician with a specialist interest in HIV/AIDS. It assumes that there is availability of appropriate
information for patients, and that they are receiving specific advice on therapy options as well as general aspects of care, with
attention to psychological support as needed. It is also assumed that they are already being offered regular monitoring with
CD4 counts and appropriate prophylaxis against Pneumocystis, Toxoplasma, Mycobacteria, Fungi and herpesviruses.
Specific Drugs by Category:
Nucleoside Analogues (NA) | Non-Nucleoside RT Inhibitors (NNRTI) | Protease Inhibitors (PI) | |
| Didanosine (ddI) | [Delavirdine] | Indinavir | |
| Lamivudine (3TC) | [Loviride] | Ritonavir | |
| Stavudine (D4T) | [Nevirapine] | Saquinavir | |
| Zalcitabine (ddC) | [Nelfinavir] | ||
| Zidovudine (ZDV) |
I) To initiate antiretroviral therapy,
II) To assess the initial impact of such therapy and, in due course,
III) To determine when to change therapy.
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AIDS Treatment Project welcomes the PACT guideline as a flexible framework providing
optimal care for people with HIV. Further guidelines and a standard of care document will be presented by the British HIV Association
in April. |
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ANTIVIRALS
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Boehringer-Ingelheim, the manufacturers of nevirapine have announced availability to this drug on a named patient basis in the UK. Nevirapine is the only member of a class of antiretrovirals, non-nucleoside reverse transcriptase inhibitors (NNRTIs), to have received licensing approval anywhere in the world (USA). As yet there are no licensed NNRTIs available for prescription in Europe.
Approval in the US was granted by the FDA for the use of nevirapine in combination with nucleoside analogues in the treatment of HIV-1 infected adults who have experienced clinical and/or immunological deterioration. This approval was based on analysis of changes in surrogate endpoint data from clinical trials of up to 48 weeks duration. A large scale trial (BI 1090) evaluating the effects of nevirapine on clinical progression of HIV-1 infection is ongoing in the US and other countries around the world, including several centres in the UK.
Registration in Europe is planned for 1997. Whilst that process is being completed nevirapine has now been made available, on a named patient basis, to physicians who feel their patient may benefit from treatment with nevirapine.
It is important that patients receive nevirapine only as part of combination antiretroviral therapy and never as monotherapy. It is also important that patients whose disease status is deteriorating do not have nevirapine added in to an existing antiretroviral therapy or therapies. In such situations the existing therapy should be changed so that the patient always receives two antiretrovirals that have not previously been prescribed in addition to nevirapine.
For a full information pack and named patient request forms please contact Dr John Drake, Boehringer-Ingelheim Ltd. Tel: 01344 741468.
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While the indications are that the most effective use of NNRTIs may be as part of a combination in initial therapy this programme does provide for
access to nevirapine as a component of a salvage combination. Encouraging results from Washington on the use of a combination of indinavir/3TC/nevirapine
in advanced heavily pre-treated patients (see DocFax Issue 16) would seem to support its inclusion in combinations
where the patient is naive to at least two of the agents. Information on considerations for dosage adjustments for concurrent
administration of protease inhibitors is included in the information pack, as is a copy of the current US package insert
giving details of potential adverse reactions (around 6% of patients experience a severe skin rash with nevirapine).
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In HIV-infected patients with a history of at least six months of zidovudine therapy, switching to stavudine significantly "...decrease[d] the rate of clinical progression." The finding is reported by Dr. Spotswood L. Spruance of the University of Utah in Salt Lake City and the Bristol-Myers Squibb Stavudine/019 Study Group in the current Annals of Internal Medicine.
Their trial involved 822 HIV-positive subjects with CD4+ counts between 50 and 500 cells/mm3 who had already completed at least 6 months of zidovudine therapy. Dr. Spruance's group found that stavudine significantly delayed the progression of HIV disease compared with zidovudine, and these "...effects of stavudine could be seen across all patient strata defined by CD4+ cell counts at baseline and stage of HIV disease."
Stavudine use was associated with a low frequency of adverse reactions and drug interactions. Neuropathy occurred more frequently when patients were on stavudine compared with zidovudine, but the neuropathy "...resolved completely in many patients after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose." And the dosing schedule - twice daily with or without food -- was convenient, according to Dr. Spruance, who also observed that stavudine penetrates the blood-brain barrier.
"Stavudine is an important agent to be considered for inclusion in combination therapy," Dr. Spruance writes. Currently, clinical trials of stavudine administered in combination with a number of protease inhibitors are under way.
Ref: Ann Intern Med 1997;126:355-363.
Source: Aegis
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This study was first presented in 1995. While it does not represent the optimal use
of d4T, which is as a combination agent, it does support the use of d4T in persons who have been previously treated with ZDV.
Results from combination therapy including d4T are now being presented which also encourage its use (see Washington reports in DocFax
16). Peripheral neuropathy with d4T occurs at a similar rate to ddC and is more likely in patients with advanced disease.
It is usually slowly reversible on prompt cessation of therapy. |
The International Association of Physicians in AIDS Care (IAPAC) has produced a new booklet written by Dr Marty Markowitz of the Aaron Diamond AIDS Research Centre in New York aimed primarily at patients titled - Combination Therapy for HIV Infection: Why to use more than one drug, and which drugs to use.
The booklet in electronic format is also available on the IAPAC website at: http://www.iapac.org/consumer/combbk.html
German researchers report that combination ZDV/3TC treatment results in a "strong and sustained" reduction in viral load in HIV-positive children. This effect is similar to that seen in adults, according to Dr. Brigitte Solder of Ludwig Maximilian's-University in Munich and colleagues.
Dr. Solder divided 10 children and adolescents with HIV infection into one of two groups; the first group received ZDV and ddI; the second group received ZDV and 3TC. After treatment began, the subjects receiving ZDV/ddI had a "...slight trend of a decreasing ratio of viral load per number of CD4 cells," while the subjects receiving ZDV/3TC had a significantly decreasing ratio, "...indicating a marked suppression of viral turnover with ZDV/3TC treatment."
While both regimens resulted in increases CD4 cell levels and decreases in HIV copy number, she found that "...these effects were much more pronounced and prolonged in the combination of ZDV/3TC than with ZDV/ddI. Although the two groups were not comparable for statistical purposes, she nonetheless believes these results warrant "urgent" clinical evaluation of ZDV/3TC combination therapy in children with HIV infection.
Ref: J Pediatr 1997;130:293-299.
Source: Aegis
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Treatment options for HIV-infected children remain limited with only ZDV and ddI licensed
for paediatric use. This study must be interpreted with caution due to limited numbers of subjects but the results are welcomed.
3TC has good tolerability and convenience of administration and in combination with ZDV would represent an attractive further
option for the treatment of children. |
Italian researchers report that the peripheral neuropathy that can develop in AIDS patients taking antiretroviral nucleoside analogues correlates with an acetyl-carnitine deficiency. Dr. Giuseppe Famularo of the University of L'Aquila in Rome and colleagues therefore suggest that the "...significance of acetyl-carnitine deficiency in neuropathic patients needs to be further investigated."
Dr. Famularo evaluated serum levels of acetyl- and total carnitine in 12 AIDS patients diagnosed with axonal peripheral neuropathy while being treated with ddI, ddC or d4T, potentially neurotoxic nucleoside analogues. These subjects were then compared with a matched set of controls who did not experience neurotoxic effects with nucleoside analogues.
He found that the subjects who developed neuropathy had "...reduced levels of acetyl-carnitine in their sera. By contrast, subjects who did not experience peripheral neuropathy while taking ZDV or ddI had normal levels of acetyl-carnitine."
However, all of the subjects had normal serum carnitine levels, suggesting that "...certain pathways of carnitine metabolism, such as the acetylation of carnitine to acetyl-carnitine, are impaired in these subjects, probably as a result of the toxicity of ddI, ddC and d4T." He also points out that "...normal levels of total carnitine and albumin point to the preserved nutritional status of these subjects and support the view the that acetyl-carnitine deficiency observed is independent of nutritional factors."
Based on these findings, Dr. Famularo believes that since exogenous supplementation with acetyl-carnitine has no toxic effects, it may be useful in preventing or treating neurotoxicity in AIDS patients receiving nucleoside analogues.
Ref: AIDS 1997;11:185-190.
Source: Aegis
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Acetyl-carnitine is available in the UK. Evaluation of intervention in persons with peripheral neuropathy is now required.
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A therapeutic problem associated with the oral administration of the protease inhibitor saquinavir is poor absorption. California researchers now report that the P-glycoprotein pump may be the mechanism preventing absorption of saquinavir in the gut.
In vitro experiments show that saquinavir is initially taken up by gut cells, but it is then pumped back out by P-glycoprotein. Dr. Carla Washington reported these results at the 1997 meeting of the American Society for Clinical Pharmacology and Therapeutics, San Diego, California.
The Stanford University investigators first noted that saquinavir was deactivated by the cytochrome P450 enzyme system. This led them to investigate the effect of the P-glycoprotein system on saquinavir. Through a series of studies in which various chemotherapeutic agents were used to compete with saquinavir, they found strong evidence that saquinavir is recognised by P-glycoprotein. However, direct evidence that saquinavir fails to accumulate in the blood because of P-glycoprotein is still lacking.
They also noted that another protease inhibitor, ritonavir, similarly binds to P-glycoprotein, but ritonavir appears to be able to be taken up into the blood anyway. The third licensed protease inhibitor, indinavir, shows no evidence of P-glycoprotein binding.
Team leader Dr. Terrence Blaschke speculates that blocking P-glycoprotein may lead to improved drug absorption. He also suggests that P-glycoprotein may have a role in preventing protease inhibitors from crossing the blood-brain barrier.
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OPPORTUNISTIC ILLNESSES
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AIDS experts at the University of California at San Diego report that detection of human cytomegalovirus DNA (HCMV DNA) in plasma using PCR identifies persons at risk of CMV disease, and that this assay is more accurate than urine or blood leukocyte cultures.
Dr. Mike Shinkai and others followed 94 participants in protocol 181 of the AIDS Clinical Trials Group for 12 months. They obtained blood and urine specimens from the patients every three months. Twenty-six (28%) patients developed HCMV disease during follow-up.
By qualitative PCR, the investigators detected HCMV DNA in the plasma of 41 patients, 24 of whom developed HCMV infection. The sensitivity and specificity of plasma PCR (89% and 75%, respectively) were higher than for either urine (85% and 29%) or leukocyte (38% and 74%) cultures.
Further quantitative PCR analysis of positive plasma samples showed that the mean peak level of HCMV DNA was 1510 copies/mm3 in the patients who developed disease compared with 161 copies/mm3 in those who did not.
While high levels of HCMV DNA in plasma identify those at highest risk for HCMV disease, Dr. Shinkai and colleagues note in the current issue of The Journal of Infectious Diseases that "some persons appear to maintain low levels of HCMV DNA in their plasma despite development of disease."
They add that their observations "...indicate that persons with advanced HIV infection may have active HCMV infection for months before clinically recognised HCMV disease." The investigators suggest that these findings may help guide "...decisions regarding HCMV prophylaxis and treatment."
Ref: J Infectious Dis 1997;175:302-308.
Source: Aegis
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CMV viral load testing is currently only available as a research tool in the UK, mostly
via the Royal Free Hospital. Development in a kit form may encourage wider use. Availability of a predictive test provides
the potential for pre-emptive therapy in patients at high risk. Trials to assess this approach are now planned.
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For patients with advanced AIDS and Kaposi's Sarcoma (KS) who do not respond to first-line treatment for KS, or who develop high levels of toxicity, pegylated-liposomal doxorubicin offers an alternative, according to members of the DOXIL 30-12 study group.
Based on reports that pegylated-liposomal encapsulation enhances doxorubicin delivery to KS tumour while resulting in lower levels of toxicity, Dr. Donald W. Northfelt of Palm Springs, CA and colleagues conducted an open trial of pegylated-liposomal doxorubicin in 53 AIDS patients with KS. In February's issue of the Journal of Clinical Oncology, Dr. Northfelt reports that all the patients were unresponsive to conventional treatment or developed intolerable toxicity. The subjects received 20 mg/m2 of pegylated-liposomal doxorubicin every three weeks. Dr. Northfelt found that 19 patients experienced a partial response with a median duration of 128 days. One subject had a complete response to treatment that lasted 134 days. Most of the patients experienced at least some clinical benefits with pegylated-liposomal doxorubicin; the most common were loss of oedema, improved lesion colour, flattening of lesions and relief of pain. Forty percent of the patients developed leukopaenia during treatment, and 15% experienced nausea and/or vomiting.
Overall, Dr. Northfelt's' group concludes that pegylated-liposomal doxorubicin may be a useful salvage treatment for patients with advanced AIDS who have not responded well to first-line treatment for KS.
Ref: J Clin Oncol 1997;15:653-659.
Source: Aegis
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DOXIL is licensed in the UK under the trade name CAELYX. Due to its high cost it is
currently often used only as second or third line therapy for KS.
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Use of "...[i]ntralesional hyaluronidase enhances vinblastine in the treatment of cutaneous lesions of KS [Kaposi's' sarcoma] without adding to the systemic toxicity," according to members of the Military Medical Consortium for the Advancement of Retroviral Research.
Hyaluronidase is an agent used to enhance dispersion of drugs through tissue, according to Dr. Kathleen J. Smith of Walter Reed Army Institute of Research in Bethesda. This agent has been used to increase the area of local anaesthesia and to enhance the chemotherapeutic effects of drugs, she writes in the February issue of the Journal of the American Academy of Dermatology.
Dr. Smith and colleagues evaluated six patients with multiple cutaneous plaque lesions and tumours of KS. The subjects received intralesional vinblastine, intralesional hyaluronidase, or intralesional hyaluronidase followed by intralesional vinblastine.
The investigators discovered that the greatest clinical regression of KS tumour occurred when intralesional hyaluronidase was administered before intralesional vinblastine treatment. "In addition, lesions treated with hyaluronidase and vinblastine recurred less often than those treated with vinblastine alone and showed no evidence of residual KS in two patients undergoing biopsy between 4 and 6 months after therapy."
They conclude that combination intralesional hyaluronidase and intralesional vinblastine can improve KS treatment, particularly for patients with larger cutaneous lesions. "The best candidates for this therapy would be patients with fewer than 10 lesions who have more stable disease."
Ref: J Am Acad Dermatol 1997;36:239-242.
Source: Aegis
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Intralesional therapy is an attractive option for cosmetic treatment of small numbers
of skin lesions, single new lesions and oral lesions. It is most effective when used at the time of appearance of the lesion.
In these circumstances the toxicitys associated with systemic therapy may be avoided. Hyaluronidase as an injectable
and in ointments is available in the UK.
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PATHOGENESIS
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Australian researchers say they have identified an HIV-positive homosexual man who is homozygous for the CCR5 mutation that has been associated with protection against HIV infection. Dr. Robin Biti and colleagues at Westmead Hospital in Australia describe this patient in a letter published in the March issue of Nature Medicine.
Last year researchers presented "...compelling evidence for a high level of protection against HIV-1 infection in homosexual men who are homozygous for the chemokine receptor 32 base pair deletion mutation," the investigators write. However, this case "...clearly suggests that CCR5 is not essential as a coreceptor for all primary HIV infection."
The patient in question, who is of European descent, was the only one with this genotype out of 265 HIV-1-positive patients evaluated in the Sydney area, "...indicating that whilst it is a very rare occurrence, individuals with this genotype can be infected with HIV."
The rate of disease progression in this patient is unclear. Although he is thus far asymptomatic, Dr. Biti and colleagues say that "...he does not appear to be a long term non-progressor..." based on his decline in CD4 count.
Ref: Nature Medicine 1997;3:252-253.
Source: Aegis
Abstract: Recent studies have identified several coreceptors that are required for fusion and entry of Human Immunodeficiency Virus type 1 (HIV-1) into CD4+ cells. One of these receptors, CCR5, serves as a coreceptor for nonsyncytium inducing (NSI), macrophage-tropic strains of HIV-1, while another, fusin or CXCR-4, functions as a coreceptor for T cell line-adapted, syncytium inducing (SI) strains. Using sequential primary isolates of HIV-1, we examined whether viruses using these coreceptors emerge in vivo and whether changes in coreceptor use are associated with disease progression. We found that isolates of HIV-1 from early in the course of infection predominantly used CCR5 for infection. However, in patients with disease progression, the virus expanded its coreceptor use to include CCR5, CCR3, CCR2b, and CXCR-4.
Use of CXCR-4 as a coreceptor was only seen with primary viruses having an SI phenotype and was restricted by the env gene of the virus. The emergence of variants using this coreceptor was associated with a switch from NSI to SI phenotype, loss of sensitivity to chemokines, and decreasing CD4+ T cell counts. These results suggest that HIV-1 evolves during the course of infection to use an expanded range of coreceptors for infection, and that this adaptation is associated with progression to AIDS.
Ref: Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. J. Exp. Med. 185(4): 621-628
(Feb 17, 1997).
A multicenter team reports that it may have pinpointed events that mark the progression of HIV infection to AIDS.
Dr. Conrad C. Bleul, of Harvard Medical School in Boston, Massachusetts, and researchers at LeukoSite, in Boston and at the University of Pennsylvania, provide background in the Proceedings of the National Academy of Sciences for their elucidation of the role played by two chemokines in HIV infection. CCR5 is the "...receptor of choice..." used by HIV during the initial stage of infection, they say, and CXCR4 is used by more virulent HIV strains during more advanced stages of HIV infection. HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes, according to the investigators.
And Dr. Bleul's team reports a new discovery, according to a Proceedings press release. "CXCR4 receptors are found primarily on immunologically naive T cells that have had no prior exposure to foreign antigens. CCR5 receptors, on the other hand, show up on previously activated "memory" T cells." Dr. Bleul writes that "...[t]aken together, these findings suggest that HIV's target cell population may shift to a different T-cell subset during the transition to AIDS."
Ref: Proc Natl Acad Sci USA 1997;94:1925-1930.
Source: Aegis
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The identification of coreceptors has led to consideration of their potential utility
as sites of drug or vaccine intervention. Studies such as the above sound a note of caution as the flexibility of HIV coreceptor
use is revealed. |
Glutathione (GSH) deficiency in patients with HIV infection is a strong predictor of poor survival, according to a report published in the Proceedings of the National Academy of Sciences.
Stanford University researchers have also discovered that, when used in combination with CD4 cell counts, glutathione levels can provide a more accurate means of tracking the progression of HIV disease.
Dr. Leonard A. Herzenberg and colleagues in Stanford, California, report the results of in vitro studies in which they evaluated blood samples from 204 HIV-positive patients. They found subjects with glutathione deficiency had a "...markedly decreased survival 2-3 years after baseline data collection..." when compared with subjects without glutathione deficiency. Patients with CD4 T cell counts below 200/mm3 also had lower glutathione levels compared with subjects in earlier stages of HIV infection.
"What we show for the first time in this work is that people with HIV who have lower glutathione levels have a much lower probability of surviving over the course of three years than do people with normal glutathione levels," Dr. Herzenberg said in a press release. He has presented preliminary reports of these findings at recent meetings.
Dr. Herzenberg also found that glutathione levels were replenished following oral administration of the glutathione product N-acetylcysteine, which suggests "...a potential intervention to relieve this impairment." If these findings can be replicated, Dr. Herzenberg writes, "...they will provide the foundation for the use of N-acetylcysteine as an inexpensive, nontoxic adjunct therapy for HIV/AIDS, potentially valuable even in remote locations where only minimal medical supervision is available."
Dr. Herzenberg's group believes that HIV-positive subjects should avoid excessive exposure to UV irradiation, alcohol and drugs, such as acetaminophen, which are known to deplete glutathione levels. And, based on these findings, Dr. Herzenberg and others have asked the FDA to require drug companies to include labelling on products known to deplete glutathione because of the potential hazard to HIV-positive patients.
Ref: Proc Natl Acad Sci USA 1997;94:1967-1972.
Source: Aegis
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Previous small intervention studies with n-acetyl cysteine (NAC) failed to demonstrate
benefit but the above results strongly warrant further investigation. |