DOCTOR FAX

ISSUE 47 12th June 1998


Sourced Compiled and Edited by Paul Blanchard

Medical Consultant

Contents


OPPORTUNISTIC ILLNESS



Wasting/Endocrine Disorders: A Review


There have been two major developments in the nutritional management of HIV-infected people and both are related to the application of potent combinations of antiretroviral agents: The prevalence and severity of severe malnutrition has declined sharply ov er the past two years. However, nutritional status may not return to normal in treated patients, but rather evolve to a condition characterised by the development of truncal obesity, associated with several metabolic alterations.

Prevalence

Advances in the antiretroviral treatment of HIV infection, coupled with developments in the prophylaxis and therapy of opportunistic infections, have changed the outlook for HIV-infected individuals. Death rates from AIDS fell significantly in 1997 as com pared to 1996. Clinical studies have shown that the incidence of weight loss also has decreased substantially compared to 1995. Incidence rates for PCP, CMV, MAC, cry ptosporidiosis, and microsporidiosis, among other disease complications, also have fallen substantially. These infections had been frequent causes of severe wasting in the past. Furthermore, reports of spontaneous resolution of microsporidiosis and crypto sporidiosis (when patients are placed on potent antiviral therapy) have appeared in the literature, attesting to the fact that effective viral suppression may lead to some degree of immune reconstitution. However remarkable they may be, these advances are o f course limited to patients taking these therapies, so that much of the developing world is excluded from these benefits. In addition, a significant percentage of patients are unaware of their HIV infection until such time as the onset of a disease compl ication which is associated with wasting. Furthermore, the fate of patients whose antiretroviral regimens fail is uncertain. Some patients have begun to lose ground nutritionally, while others appear to remain clinically stable despite high viral loads.

Composition of Lost Weight in HIV Infection

Continuing studies of body composition have refined our understanding about the composition of lost weight in HIV infection. As noted above, the number of severely malnourished patients has declined. The loss of body cell mass--a somewhat intangible conce pt--is related directly to a loss of skeletal muscle--which is very tangible. Tissue depletion is associated with decreased functional status, especially physical performance. The wasting process appears to differ in men and women, with women losing proportionately more fat than do men. The cause is uncertain and could be related simply to the fact that healthy women have more fat to lose; alternatively, the effect could be related to the development of functional hypogonadism, which has been seen in other stressed states as well as in severe malnutrition.

Pathogenesis

Several studies suggest that nutritional alterations are a direct result of HIV infection, or the body's immune response thereto. Studies have sho wn body cell mass depletion without weight loss in intermediate stage HIV-infected patients, elevated resting energy expenditures in asymptomatic HIV-infected subjects, and a direct relationship between plasma HIV RNA and resting energy expenditure. Recen t studies also have correlated recent weight loss with plasma viraemia.
It is likely that the mechanism of weight loss related specifically to HIV is the same as for any chronic infectious disease, i.e., it occurs as a consequence of proinflammatory cytokine activities namely, tumour necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6). In addition to their well-known effects on the inflammatory response, such as producing fever, anorexia, and stimulating the acute phase response, these cyt okines also affect intermediary metabolism, including the promotion of protein depletion and fat synthesis. The study of cytokines in disease has advanced rapidly in experimental systems, but analogies in HIV infection and many other conditions are diffic ul t to demonstrate. This may be due to the extremely short half-lives of many of these cytokines in the circulation, or to the fact that many have local actions (autocrine or paracrine) whose effects are not well represented by serum or plasma concentration s. Several surrogate markers for cytokine activity have been applied, such as the use of soluble receptors, circulating antagonists, etc. Studies in Africa and the U.S. have employed these surrogate markers in plasma and in urine to document the heightene d immune reactivity in HIV infection and its association with wasting.
Several studies over the past five years have documented alterations in fat metabolism with the frequent development of hypertriglyceridemia. Other studies have documented protein and skeletal muscle depletion, which in some cases are associated with decr eased protein synthesis and increased protein degradation. Hypogonadism, a frequent development in HIV-infected individuals, is more common in late stage disease, and may be a response to either the stress of infection or to malnutrition. Testosterone replacement may have effects upon body cell mass, mood, and sexual arousal.

Current Treatment Goals

The obvious goal of treatment is to restore the balance between protein (muscle) synthesis and degradation, by either stimulating the former by the use of anabolic agents, or by retarding the latter by the use of cytokine inhibitors such as thalidomide.
Studies of anabolic agents in HIV-infected people was spurred on by the results of trials of both non-volitional feeding as well as appetite stimulation, which demonstrated disproportionate repletion of fat, and not body cell mass. Since weight loss is associated with disproportionate loss of body cell mass, and cycles of weight loss and gain ma y occur during the disease course, patients tend to have chronic depletion of body cell mass and muscle with concurrent increase in relative amount of fat (sarcopaenia). Several studies have evaluated the effects of anabolic steroids or growth hormone in HIV infection and have documented increases in lean mass, rather than fat. Current studies attempt to demonstrate clinical, i.e. functional, benefits from these therapies, or to examine these therapies as part of a combination regimen.
The potential benefits of cytokine inhibition have long been recognised. Prior studies involving pentoxifylline, an inhibitor of TNF, failed to show clinical benefits. Thalidomide also has been shown to lower TNF production, in this case through enhanced degradation of TNF mRNA. The drug is being applied in a variety of conditions associated with inflammation and excess cytokine production. It has been approved for use in erythema nodosum leprosum, a highly inflammatory form of leprosy.
Thalidomide also has been shown to be effective in the treatment of oral or oesophageal aphthous ulcers associated with HIV infection. Two studies, one in Thailand and the other in Mexico, evaluated thalidomide as adjunctive therapy in HIV-associated tube rculosis, and both studies documented great er weight gain in thalidomide-treated patients. A double-blind, placebo-controlled trial comparing two doses of thalidomide to placebo in the treatment of malnutrition related to HIV infection has been carried out in the US. The results showed weight gain in treated subjects. Body composition studies suggested that the majority of the weight gained was lean mass instead of fat. There were treatment-associated side effects, including somnolence and rash. An apparent rise in plasma viral burden in the treat ed group was also noted during therapy. This unnerving result, which also has been seen in other thalidomide studies, is of uncertain significance, since the actual increases were small (averaging 0.3 log). The major current question is whether such an effe ct would be seen in patients if they were also receiving effective combination antiretroviral therapy. Studies to address this important question are in the planning stage.

Alterations in Body Shape Seen with HIV Infection and Antiretroviral Therapy

The m ost novel nutritional problem to be recognised over the past two years involves the increasing recognition of a characteristic alteration in the body's shape which is seen in patients receiving combination antiretroviral therapy, usually including proteas e inhibitors. Such patients first were recognised about 18 months ago because of a sudden increase in waist size (truncal obesity), and in some cases because of the development of a fatty mass (buffalo hump) at the back of the neck. These findings are cla ss ic signs of Cushing's syndrome and are related to chronic elevations in cortisol secretion, but here, serum cortisol levels were typically normal. A report from the FDA also noted reports of diabetes mellitus developing in a number of patients receiving p rotease inhibitors, with reversal in some patients upon discontinuation of the medications. Some of these diabetic patients also developed truncal obesity. Recognition of the syndrome has spread widely, although very little data has been published.
There ar e a variety of pseudonyms for this syndrome, usually aimed at one or another pharmaceutical company! The one published paper terms the changes "peripheral lipodystrophy". The most obvious change is an increase in waist size, but several other changes may develop as well: These include thinning of the arms and legs, increased wrinkling of the face (especially in the nasolabial folds), weakness, muscle wasting in the extremities, low serum testosterone concentrations, hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia and hypertension. It should be remembered that some of these changes, such as hypertriglyceridaemia and low serum testosterone concentrations, are commonly seen in HIV-infected people regardless of therapy.
The process can also affect females; here, the most notable changes in addition to increased waist size are narrowing of the thighs and breast enlargement. These changes are not necessarily accompanied by weight gain. It is bizarre that the changes often seem most marked in patients who are otherwise responding well to therapy. Many patients have undetectable plasma viral burdens, and have enjoyed a substantial rise in CD4+ lymphocyte counts, with overall good general health.
Several studies of this syndrome were presented at the 5th Conference on Retroviruses and Opportunistic Infections in February 1998. An Australian group (abstract 410) recognised the body composition and metabolic changes in their treated patients and hyp othesised that they were due to acquired insulin resistance. They studied subjects who were receiving or not receiving protease inhibitors, and compared these to controls. They documented increased truncal fat in a majority (64%) of their protease inhibitor-treated subjects using the technique of dual X-ray absorpt iometry. They also found evidence of insulin resistance, although clinically apparent diabetes mellitus was very uncommon. The investigators also found evidence of a possible molecular mechanism for the change: An amino acid sequence in the catalytic site of HIV protease was found to have a significant homology with a low density lipoprotein (LDL) receptor-like protein. These results would tend to implicate the protease inhibitors themselves in the development of this problem.
In contrast, a cross sectional study from New York (abstract 408) found a prevalence of truncal obesity of only 5%. Another study, from Ottawa, noted this finding in only about 2% of their patients receiving protease inhibitors (abstract 411). Neither of these two studies used sophisticated measures of body composition, and conceivably might have missed the changes.
A group from the NIH (abstract 413) documented truncal obesity in their patients using a CT scanning technique. In this study, fat in the subcutaneous versus the intraperitoneal (visceral) compartment space was determined from a single CT cut taken at the L4-L5 level. Normally, much more fat is found in the subcutaneous than in the visceral compartment, especially in women. The results of this study showed a relative increase in visceral fat in patients who had been on protease inhibitor therapy for more than six months and who had experienced symptoms. There were no relationships among visceral fat, body weight, and body mass index, but associations among increased visceral f at, hypertriglyceridaemia and hypercholesterolaemia were found.
Two additional studies, from Atlanta (abstract 407) and from San Francisco (abstract 409) studied small series of patients with buffalo humps. Cushing's disease was ruled out by normal dexameth asone suppression tests. In one study, development of a buffalo hump was not limited to patients receiving protease inhibitor therapy (abstract 409).
Several studies have documented hypertriglyceridaemia, as well as insulin resistance (abstract 414) as a feature of protease inhibitor therapy, despite apparently beneficial virologic and immunologic effects. In contrast, the incidence of clinical diabete s mellitus in patients receiving protease inhibitors was low in two studies (abstracts 415 & 416). When it occurs, the diabetes may be severe and associated with ketoacidosis. Insulin or oral hypoglycaemic agents may be required for control of blood sugar.
Our own studies have analysed the body composition alterations using MRI scans as well as anthropometric and other body composition methodologies which analyse regional body composition. Accumulation of fat in the visceral compartment, instead of under th e skin has been documented by MRI scans. As noted above, not everyone with this alteration is receiving protease inhibitor therapy, but all have low or undetectable plasma viral burdens.
Of course, many patients on protease inhibitor therapy have absolutely no evidence of the syndrome. Anthropometric measures have been used to evaluate body composition in HIV-infected subjects seen in the modern treatment era (since January 1996) compared to those seen 1995 and prior. Several anthropometric measurements show that many "modern era" patients had a relative increase (lesser decrease) in visceral fat compared to su bcutaneous fat. However, "previous" HIV-infected patients also had similar changes, though it was less noticeable as they generally had less fat overall, and some had characteristics identical to those in the "modern era".

Nutritional And Metabolic Alterations Seen During Antiretroviral Therapy
Truncal obesity
Buffalo hump
Enlarged supraclavicular fat pads
Breast enlargement in women
Decreased skinfold thickness in the arms, legs, and face
Peripheral muscle wasting
Low serum testosterone concentration
Hypertriglyceridaemia
Hypercholesterolaemia
Hyperglycaemia
Diabetes mellitus
Hypertension

How Can "The Syndrome" Be Managed?

It is unclear as to whether or not we are witnessing a new phenomenon. A similar syndrome of truncal obesity and metabolic abnormalities, including insulin resistance, has already been described in HIV-negative subjects, and is termed "Syndrome X." The fi ndings in these HIV-infected individuals are similar to those of Syndrome X, which is worrisome, since that syndrome is associated with accelerated cardiovascular disease.
However, we should avoid a rush to judgement. There are many unanswered questions:

At present, there is absolutely no indication for discontinuing antiretroviral therapy when these changes occur. Certainly, aggressive treatment is indicated for diabetes, hypertension and significant hyperlipidaemia. Other measures to prevent possible at herosclerotic disease, such as cessation of cigarette smoking, moderation of food intake, use of low dose aspirin and omega-3 fatty acids, and institution of aerobic exercise, may be considered. There is no hard evidence, despite an increasing number of claims, that any current treatme nt can prevent or reverse the changes.
Ref: 8th Clinical Care Options for HIV Symposium
Author: Donald Kotler, M.D.
Fully referenced article is available on the internet at:

http://www.healthcg.com/hiv/journal/scottsdale98/10.html


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ANTIRETROVIRALS



ZDV treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria: Antioxidant vitamins offer protection


High doses of the antioxidant vitamins C and E may prevent the myopathy caused by mitochondrial damage associated with zidovudine therapy in HIV-positive patients, according to a report by Spanish researchers. They therefore suggest that antioxidant vitam in supplementation be a part of any treatment regimen that includes zidovudine.
"AIDS patients who receive zidovudine (ZDV, Retrovir symbol 212 "Symbol" 10 ' and component of Combivir symbol 212 "Symbol" s 10 ') frequently suffer from myopathy," Dr. Jose Vina and colleagues at the Universidad de Valencia point out in a paper to be published in the June 15th issue of the Journal of Clinical Investigation . "This has been attributed to mitochondrial (mt) damage and specifically to the loss of mtDNA."
In the current study, Dr. Vina's group evaluated urine samples from 23 asymptomatic HIV-positive patients with an average age of 30 years who were receiving ZDV. They also evaluated HIV-positive subjects who had not been treated with ZDV and healthy controls. In addition, some of the ZDV-treated HIV-positive subjects were given antioxidant vitamin supplements for 1 month. The re searchers used urine levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) as a marker for DNA oxidative damage.
Compared with the untreated HIV-positive patients and the controls, Dr. Vina's group found that the ZDV-treated HIV-positive subjects had hig her urinary excretion levels of 8-oxo-dG. However, they also found that 8-oxo-dG excretion "...was prevented by simultaneous oral treatment with ZDV plus antioxidant vitamins (C and E)."
In addition, they noted similar effects in a mouse model. When they examined skeletal muscle mtDNA from ZDV-treated mice, they found higher levels of 8-oxo-dG compared with control mice. They also found that mitochondrial "...lipoperoxidation was...increa sed and skeletal muscle glutathione was oxidised." They believe that this may be "... due to an increased peroxide production by muscle mitochondria of ZDV-treated animals."
Based on these findings, Dr. Vina's group concludes that antioxidant supplementation "...with vitamins C and E at supranutritional doses protect against oxidative damage to skeletal muscle mitochondria caused by ZDV."
Ref: J Clin Invest 1998; June 15, 1998; 101 (12)
Source: CDC Daily News Update

Although true myopathy is now rare at current ZDV doses (250 - 300 mg bid) subclinical effects on mitochondri a may still be expected with ZDV use (these patients with raised 8-oxo-dG were asymptomatic). With such evidence of DNA oxidative damage in ZDV users but no myopathy it would now be useful to see if muscular function was affected. Studies of such markers as exercise tolerance, muscle fatigue and the effect of antioxidant vitamins should be performed to explore the clinical relevance of this damage. Doses of vitamins used in this study were not determined at publication date of this issue of Doctor Fax, bu t were stated to be supranutritional (ie. above recommended daily allowances). We will report doses used in our next issue after the JCI goes to press.

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ZDV resistant virus displays cross-resistance to other nucleoside analogues in the presence of ZDV


Eric Arts first aired this intriguing data on mechanisms of zidovudine (ZDV, Retrovir symbol 212 "Symbol" 10 ' and component of Combivir symbol 212 "Symbol" 10 ') resistance at the Resistance meeting last year (St.Petersburg 25-28 June 1997. Abstract 10. See ATP's DocFax Issue 27 ). His studied revealed that HIV, which has become resistant to ZDV displays faster reverse transcription rates overcoming the antiviral effects of ZDV. More worryingly, he also described such virus as having cross-resistance to other nucleoside analogues when in the presence of ZDV.

Abstract


Difficulties in deciphering the mechanisms of 3'-azido-3'-deoxythymidine (AZT/ZDV))-resistance by human immunodeficiency virus type 1 (HIV-1) variants are due in part to an inability t o reconstitute resistance in vitro using AZT-resistant reverse transcriptases. We decided to characterise mechanisms of AZT resistance in tissue culture infections by studying the ability of drug-resistant viruses to synthesise viral DNA in the presence o r absence of drug. Through use of PCR amplifications, we discovered an AZT-mediated stimulation of reverse transcription by AZT-resistant viruses carrying the M41L and T215Y mutations that can apparently override the inhibitory effects of AZT-5'-triphosph at e. In addition, the presence of AZT also causes viruses containing the M41L and T215Y substitutions to have diminished sensitivity to other nucleoside analogues (i.e., ddC, ddI, and d4T). This AZT-mediated cross-resistance may help to explain the virologi cal failure of treatment regimens that included ddI plus AZT or ddC plus AZT in situations in which the T215Y and/or M41L mutations were present (F. Brun-Vezinet, C. Boucher, C. Loveday, D. Descamps, V. Fauveau, J. Izopet, D. Jeffries, S. Kaye, C. Krzyano wski, A. Nunn, R. Schuurman, J. M. Seigneurin, C. Tamalet, R. Tedder, J. Weber, and G. J. Weverling, Lancet 350:983 990, 1997). Our results suggest that the use of AZT may be contraindicated in those patients for whom resistance to this compound (M41L and/or T215Y) has been demonstrated.
Ref: Journal of Virology, June 1998, p. 4858 4865

These results may explain why patients who have received prior treatment with ZDV and have M41V and/or T215Y mutated HIV respond less well to future combination therapy involving ZDV and another nucleoside analogue.

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Data show drug penetration and antiretroviral activity of Efavirenz in Cerebrospinal fluid (CSF)

Dr. Karen Tashima and colleagues at The Miriam Hospital, Brown University, Massachusetts General Hospital, Harvard University and The DuPont Merck Pharmaceutical Company today announced that six HIV-infected patients taking the investigational drug efavir enz (Sustiva TM) in dual and triple combinations, achieved HIV RNA levels in plasma and cerebrospinal fluid (CSF) below the level of detection (<400 copies/ ml).
CSF drug levels and HIV RNA were measured in these patients who took efavirenz in a combination either with ZDV and 3TC, or with indinavir, for a mean duration of 26 weeks. These data were presented at The 8th Annual Neuroscience of HIV Infection, Basic R esearch and Clinical Frontiers meeting sponsored by Northwestern University Medical School, June 3- 6, 1998.
Efavirenz levels were determined both in the CSF and in the plasma. Efavirenz levels in the CSF achieve d a mean concentration of 35.9nM. The CSF concentrations of efavirenz reflected the levels of free drug in the plasma (not bound to plasma proteins). Mean plasma viral load prior to treatment was 53,675 (range 2,985 to 108,778), and was reduced in all the six patients to below the level of detection, both in plasma and CSF at the time point studied. HIV RNA levels were evaluated using the standard Roche AmplicorTM HIV assay. Efavirenz is currently in development as a once- daily treatment and is availabl e in expanded access programmes in Europe. It is an antiretroviral of the NNRTI (non-nucleoside reverse transcriptase inhibitor) class that also includes the licensed agent nevirapine.
Efavirenz is generally well tolerated; side effects include rash, nausea, dizziness, diarrhoea, headache and insomnia. Severe rashes have been reported in less than one percent of patients. Pregnant women should not take this new medication unless the b enefit to the mother clearly outweighs the potential risk to the foetus.

These data support both prior animal studies and the clinical evidence of patient experience (CNS effects - dizziness, vivid dreams, dysphoria would seem to indicate CNS penetration). However, it remains unclear to what extent the EFV is contributing to suppression in CSF, patients on dual NA's also saw VL in CSF fall to <400 copies/ml at 12 weeks (see below). EFV would be expected to add to the durability of such CSF viral suppression (these EFV data are out to a mean of 26 weeks).

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Cerebrospinal-Fluid HIV-1 RNA and drug concentrations after treatment with zidovudine or stavudine plus lamivudine


Researchers report that zidovudine or stavudine (d4T) taken in conjunction with lamivudine reduces cerebrospinal fluid HIV-1 RNA concentrations. The researchers tested the HIV-1 RNA levels and drug concentrations in the cerebrospinal fluid of 28 antiretro viral-naive patients before and 22 individuals after 12 weeks of treatment with either zidovudine or stavudine plus lamivudine. They observed that HIV-1 RNA concen trations were undetectable in the central nervous system after 12 weeks of treatment with antiretrovirals and that drug concentrations were consistent over time. The authors note that "if these combinations can keep the rate of replication low in the lon g term, the prevention of HIV dementia is biologically plausible."
Ref: Lancet (23/05/98) Vol. 351, No. 9115, P. 1547; Foudraine, Norbert A.; Hoetelmans, Richard M.W.; Lange, Joep M.A.; et al.
Source: CDC Daily News Update

It should be noted that these dat a are only for 12 weeks of these double NA combinations and durability of viral suppression with 2 NA's is a major consideration. Double NA combinations are no longer recommended as adequate antiretroviral treatment. It is, however, encouraging that both ZDV/3TC and d4T/3TC appeared of equivalent potency in this compartment.

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Foscarnet has considerable anti-HIV-1 activity


Foscarnet, commonly used to treat AIDS-related cytomegalovirus (CMV) infection, also decreases HIV-1 plasma load, according to two reports by European investigators published in the May 1st issue of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology.
In the first report, French researchers, led by Dr. Jean-Luc Pellegrin of the Hopital du Haut-Leveque in Pessac, evaluated the effects of foscarnet in 17 AIDS patients. The subjects also had CMV, herpes simplex virus, varicella-zoster virus infection, Kap osi's sarcoma or a combination of these conditions.
Dr. Pellegrin's team found that the subjects experienced decrease s from baseline in HIV-1 load of 0.73 log copies per millilitre after 3 days of foscarnet therapy and 1.15 log copies per millilitre after 10 days. "Furthermore, reduction of HIV-1 plasma load during foscarnet therapy did not depend on the presence or abs ence of CMV disease or on a positive pp65 antigenaemia at day 0."
Based on these data, Dr. Pellegrin's team concludes that foscarnet may be useful in lowering HIV-1 levels.
In the second paper, Dr. Bengt Jacobsson and colleagues at the Karolinska Institute in Sweden evaluated the effects of foscarnet in 10 HIV-1-positive patients who had no signs of CMV infection.
The patients received a 4-week course of 50 mg three times per day of intravenous foscarnet, a reverse transcriptase inhibitor "...that is a product analogue, in contrast to the widely used nucleoside analogues," they explain.
Dr. Jacobsson's group found that HIV-1 RNA levels "...decreased from a median value of 4.7 to 2.6 [log copies per millilitre]." This effect persisted throughout the treatm ent period, but HIV-1 RNA levels reverted to baseline 1 week after treatment was discontinued. They observed no increases in CD4+ cell counts.
All of the treated patients experienced side effects, which were severe in two. "Although the nephrotoxic effect of foscarnet is well known, only 1 patient had renal impairment after 23 days of treatment," they report.
Dr. Jacobsson's group concludes that foscarnet has a direct effect on HIV-1 replication. The "impressive decrease" in plasma HIV-1 RNA and the fact that foscarnet penetrates the blood-brain barrier, makes "...foscarnet a valuable alternative in the therapy for CMV infections in AIDS patients."
Ref: J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:46-53.
Source: CDC Daily News Update

The antiretroviral effect of foscarnet has been reported as early as the late 1980 s. The anti-HIV activity was thought important to a survival advantage seen in SOCA 1 (a trial for primary CMV treatment) although this was also questioned as an effect of a biased study population. SOCA 2 (a study of foscarnet for CMV relapse) did not show any survival benefit those patients receiving foscarnet. As an i.v. drug with long infusion times and an often high incidence of adverse effects it is unlikely to find clinical applica tion as an antiretroviral. Attempts to develop oral formulations have, so far, been unsuccessful.

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Discrepant responses to triple HIV therapy not unusual

Some HIV-positive patients treated with triple-combination antiretroviral therapy may have an increase i n CD4 cell count without a significant decline in plasma HIV RNA, according to French researchers. Conversely, other HIV-positive patients may not experience an increase in CD4 cells despite a significant decrease in plasma HIV RNA.
In the May 7th issue of AIDS , Dr. Christophe Picketty of the Universite Pierre et Marie Curie in Paris and colleagues describe a prospective study of 162 HIV-positive patients. The subjects all had previous antiretroviral experience but were protease inhibitor naive. At baseline , the mean CD4 cell count was about 69/mL and the mean plasma HIV RNA level was 4.75 log 10 copies/mL.
Dr. Picketty's group found that most of the subjects, 57%, responded to triple-combination antiretroviral therapy with an increase in CD4 cell count and a decrease in viral load. However, after a mean of 10.5 months of follow-up, 17 subjects "...did not s how an increase in CD4 cell counts despite a significant decrease in plasma HIV RNA." Another 17 patients "...exhibited an increase in CD4 cell counts that did not differ in magnitude from that of responder patients, although they failed to show a significant decrease in HIV viral load throughout the follow-up period."
Dr. Picketty's group noted no differences in the frequency of AIDS-defining events between the patients with improved CD4 cell counts but no significant viral load decreases and the patients with both immunologic and virologic response.
They found that age, sex, CDC group, and baseline CD4 cell counts of less than 50mL were unrelated to discre pant responses, as were previous zidovudine monotherapy, extent of NRTI treatment before protease inhibitor therapy or the addition of a new nucleoside analogue within 30 days of the start of protease inhibitor therapy.
They believe that these findings "...raise critical questions with regard to when triple combination regimens should be changed in patients with advanced HIV disease who fail to respond to treatment, as assessed by measuring plasma HIV RNA levels."
Ref: AIDS 1998;12:745-750.

This study aga in emphasises that individuals respond individually to antiretroviral treatment and that such individual responses should be considered in treatment decisions. A mean 10.5 months of follow up with 17 vs. 145 patients makes it difficult to determine the s ignificance of these findings.

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Acute HIV syndrome after discontinuation of antiretroviral therapy given for primary infection


Dr Eric Daar and colleagues report on the case of a 38 year old man who started antiretroviral treatment with ZDV + 3TC + ritonav ir on day 5 of an acute primary HIV-infection. Plasma HIV viral load prior to treatment was 5,600,000 copies/mL (6.75 log) but no HIV antibodies were detectable as seroconversion had not occurred at this early time point.

The patients plasma HIV viral load declined to undetectable levels (<500 copies/mL) with triple therapy. Additionally, cytotoxic T-lymphocyte (CTL) activity and CD8+ cell activation was undetectable or minimal after 5 months treatment suggesting that earl y intervention negated cell mediated immune responses to the HIV.

After 6 months of treatment with various combination regimens, this patient elected to stop antiretroviral treatment due to adverse side effects. Thirty-five days later, he developed an acute illness that was indistinguishable from the acute retroviral sy ndrome. Viraemia rebounded to pre-treatment levels and memory CTL activity and high levels of CD8+ T-lymphocyte activation were detected.

The authors conclude that the second acute syndrome was likely the result of the supp ression of the primary infection at such an early stage with minimal establishment of any durable anti-HIV CTL activity. Viral replication on withdrawal of antiretrovirals was unchecked by the immune system and rapidly attained pre-treatment primary infec tion levels with the attendant clinical illness.
Ref: Annals of Internal Medicine, 15 May 1998. 128:827-829.
Report: Paul Blanchard, ATP.


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PATHOGENESIS



Multiple modes of cellular activation and virus transmission in HIV infection: A role for chronically and latently infected cells in sustaining viral replication


CD4+ T cell activation, required for virus replication in these cells, occurs in local microenvironmental domains in transient bursts. Thus, although most HIV originates from short-lived virus-producing cells, it is unlikely that chronic infection is gene rally sustained in rapid continuous cycles of productive infection as has been proposed. Such continuity of productive infection cycles would depend on efficient long-range transmission of HIV from one set of domains to another, in turn requiring the maintenance of sufficiently high concentrations of cell-free virus across lymphoid tissues at all times. By contrast, long-lived cellular sources of HIV maintain the capacity to infect newly activated c ells at close range despite the temporal and spatial discontinuities of activation events. Such proximal activation and transmission (PAT) involving chronically and latently infected cells may be responsible for sustained infection, particularly when vira l loads are low. Once CD4 cells are productively infected through PAT, they can infect other activated cells in their immediate vicinity. Such events propagate locally but generally do not spread systemically, unlike in the acute phase of the infection, bec ause of the early establishment of protective anergy. Importantly, antiretroviral drug treatment is likely to differentially impact long-range transmission and PAT.
Ref: Zvi Grossman, Mark B. Feinberg, and William E. Paul. PNAS. Vol. 95, Issue 11, 6314-6319, May 26, 1998.

Might this suggest that antiretroviral compounds active in latently/chronically infected cell lines may be essential to long-term treatment success? Lymph-node work to be presented in Geneva may support this view (watch this space!)



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LETTERS



Double PI's: The View from the Industry


I would like to comment on the latest Dr Fax (issue 45 dated 15.05.98) which contains a section on the use of saquinavir soft gel capsules in combination with ritonavir. The last paragraph with which I take iss ue states that soft gel capsules of saquinavir are a rational alternative as part of a dual combination with ritonavir.
The position of Roche Products Ltd. is that this combination and indeed other double protease inhibitor (PI) regimens should be used with caution outside of clinical trials because there is as yet insufficient evidence of efficacy and safety.
The main reason in the past for using saquinavir in combination with a potent P450 inhibitor was to improve the bioavailability of saquinavir hard ge l capsules (Invirase) by blocking metabolism in the liver. However the current summary of product characteristics (SPC) for Invirase carries a statement that at this time there is insufficient data available on efficacy and safety of this co-administration. As no recommendation on dose and schedule for either of the compounds can be made, these drugs should not be used concomitantly . Moreover although there is a potential pharmacokinetic benefit with Invirase this is not the case with the soft gel form ulation (Fortovase) which provides much higher blood levels than Invirase on its own without the need for P450 inhibition. As Fortovase does not have a product licence in the UK the SPC for Invirase should be the reference guide for PI/PI combinations un til the current position changes.
The decision therefore to use Fortovase in combination with another protease inhibitor should be taken within the context of the benefit and risk to the patient. The acid-test for benefit should be whether two PIs together are more effective than either alone and this should be considered within the context of the potential risks of the combination. Currently we don t know the answer to the benefit question but we do know the potential risks, which include resistance to b oth PIs, interactions with other commonly prescribed drugs metabolized via P450 and the whole issue of lipodystrophy, which appears to be more common with PI combinations. Many of these points and arguments are contained in an article in Treatment Update from NAM entitled Double Dilemma (May 1998 Issue 65) which we recommend to your readers.
In summary we suggest that until there is more data from randomised trials showing that combinations of saquinavir and P450 inhibitors are safe and more effective than saquinavir alone, these combinations be reserved only for situations where there are no alternatives and certainly not for first line therapy.

Yours sincerely,



John Drake MB ChB FFPM
Medical Group Manager
Medical Adviser, HIV Focus
Welwyn Garden City, May 29, 1998

PK studies have shown no advantage in combining SGC saquinavir with ritonavir instead of HGC saquinavir. Saquinavir levels appear to be raised to a ceiling by ritonavir and the more bioavailable saquinavir formulation (Fortovase) will not raise them furth er (even if this were to be desirable). However, pricing of Fortovase is likely to make it considerably cheaper (per mg of saquinavir) than the currently available Invirase. Other issues apart from pricing will also affect both patients and cl inicians decisions about whether Invirase or Fortovase should be the saquinavir formulation to choose when combining with ritonavir. Indeed, Roche are yet to confirm if Invirase will even continue to be available after Fortovase is marketed. If it is, wil l the pricing be dropped to the equivalent price per mg of saquinavir in Fortovase? If Roche fails to act on pricing it will be market forces rather than data or safety concerns which determine the formulation of choice for combining with ritonavir.

It sho uld also be remembered that p450 and bioavailability concerns are not the sole consideration in choosing a double PI combination over the single. Converting the three-times daily (with food) 18 large capsule regimen of Fortovase to a twice daily 12 capsu le (including the ritonavir!) regimen requiring no dietary restrictions is a major consideration from the patients point of view. If tolerable, this should also be expected to have a major impact on compliance.

Other, theoretical advantages of the Double P I include more rapid initial viral suppression and coverage of a wider range of both pre-existent natural polymorphisms and treatment induced mutations in the protease enzyme. Additionally, although it is widely reported that double PI s lead to increased adverse effects (such as lipodystrophy) evidence is purely anecdotal at this time. Who has the data, why don t they publish?

As failures on single PI based combination therapy continue to mount, so will the pressure and demand for double PI based first li ne therapy. As an activist based organisation we plead with Roche to cooperate in collaborative studies with other pharmaceutical companies to ensure that data is provided to allow the safe use of such combinations. As patients and consumers, we believe t he ethical imperative for safety data is yours, and should be placed above mere marketing concerns.

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