Chelsea & Westminster Hospital.
Medical Consultant
|
SIDE-EFFECTS |
A cross sectional study by French investigators has revealed that the HAART-associated lipodystrophy syndrome is related to alterations in lipid and steroid hormone concentrations.
Dr. Marie-Lise Gougeon of the Pasteur Institute in Paris and associates measured serum total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, triglycerides, VLDL triglycerides, HDL and LDL triglycerides, apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB). The concentrations of steroid hormones, including cortisol, DHEA and DHEA sulphate, androstenedione, testosterone, and dihydrotestosterone were also measured.
Thirty seven HIV-infected men were included in the study of whom 23 were assessed as having lipodystrophy by clinical examination assigning a subjective clinical score and by computed tomography scanning. A healthy donor group for comparison consisted of healthy male blood donors. All blood samples were taken after 12 hour fasting.
The lipodystrophy-positive and lipodystrophy-negative men were comparable with respect to their age and the duration of antiretroviral therapy. Both groups were also similar with regard to weight and body mass index. However, the CD4 lymphocyte count before HAART was lower, and the increase in CD4 cells under HAART tended to be higher in those with lipodystrophy. Of interest it was also found that the CD8 T cell count was significantly higher in the men with lipodystrophy compared to those without (1200 ( 560 versus 838 ( 346). Although both groups had similar viral load under HAART it was noted that the fall in viral load from baseline with therapy had been less in those men with lipodystrophy.
The biological parameters of the two groups of HIV-infected men and the healthy subjects were statistically analysed for differences between the groups and correlations between each parameter with the following results.
Lipodystrophy is associated with dyslipidaemia
Lipodystrophy is associated with insulin, glucose and leptin alterations
Correlations between hormonal alterations and dyslipidaemia
Commenting on the cortisol levels in conclusion the investigators note that..."Lipid metabolism is partly regulated by steroid hormones, including cortisol and DHEA. Several case control studies have indicated that low levels of DHEA are associated with an increase in circulating cholesterol, LDL cholesterol and ApoB levels. In addition, the administration of DHEA to healthy men was shown to reduce serum cholesterol, LDL levels and body fat, and to decrease de-novo lipogenesis." They go on to suggest that..."stabilisation, regression or even prevention of this syndrome may be induced by steroid supplementation. Administered anti-glucocorticoid (DHEA) would antagonise the lipolitic action of cortisol." They also speculate that such intervention to the hormonal network might also induce a significant decrease in the level of total serum cholesterol, a reduction in body fat and an increase in muscle mass. The prevention of vascular complications of dyslipidaemia might also be possible.
Ref: Christeff N & Gougeon L et al. Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations. AIDS 13: 2251-2260, 1999.
|
Lipid metabolism and fat mass distribution are partly regulated by steroid hormones such as glucocorticoids and androgens, which influence adipocyte lipolysis and lipogenesis by their action on several lipases. It has been previously observed that in HIV-infection, the serum cortisol levels are increased at all stages of disease. In contrast, androgens, particularly DHEA, are elevated at early stages of HIV-disease and then dramatically decrease in later stage disease. These adrenal steroid modifications in late stage disease lead to an important rise in the cortisol:DHEA ratio, associated with the loss of fat-free mass and fat mass. It is this same rise in the cortisol:DHEA ratio that has been linked with the occurrence of lipodystrophy in this study. Paradoxically when other parameters are improving under the influence of HAART the cortisol:DHEA ratio acts as if late stage disease were still present. Outcome trials of DHEA supplementation in lipodystrophy will now be needed to determine if correcting the cortisol:DHEA ratio would have any impact on the clinical manifestation of this complication of HIV therapy. DHEA supplements are available in pharmacies and health food suppliers in the US, but not in the UK. Internet sources are also available. Supplementation with 50mg daily to elderly men has been shown to return blood levels to the normal range seen in young adults. DHEA supplementation has also been found to reduce total, HDL and LDL cholesterol in some studies. DHEA effects appear to be sex specific, and results in men cannot be extrapolated to women. Indeed some DHEA effects seen in women are not seen in men and vice versa. |
Low levels of dehydroepiandrosterone sulfate (DHEAS), but not low testosterone levels, are associated with a poor prognosis in HIV-positive men, according to a report in the October 1st Journal of Acquired Immune Deficiency Syndromes.
Dr. Stephen Ferrando and colleagues, from Cornell University Medical College in New York City, compared DHEAS and testosterone levels with markers of HIV disease in 169 HIV-positive men over a 12-month period.
Mean DHEAS levels were lowest among the men with the most advanced stages of HIV illness, the authors report. "DHEAS was positively correlated with CD4 cell count and inversely correlated with log10 HIV RNA," they write. "DHEAS was negatively associated with severity of HIV symptoms...but not with fatigue or [Beck Depression Inventory scores]." Total testosterone levels showed no such correlations, although free testosterone level was inversely correlated with HIV RNA levels.
DHEAS was the only significant predictor of the number of HIV symptoms in a multiple linear regression model, the report indicates. In contrast, DHEAS did not significantly predict the change in HIV symptoms over the course of a year.
Both DHEAS below 96 µg/dL and CD4 count below 200 cells/µL predicted incident opportunistic infections, malignancies, or AIDS-related death over 1 year, the report indicates.
The investigators found that DHEAS increased after the initiation of protease inhibitor therapy. "This study may be the first to suggest a restorative effect of antiviral therapy for any hormone," they propose. "Although this finding awaits replication in a controlled clinical trial and its clinical significance is unclear, it raises the question of whether DHEAS may be used as an adjunctive measure of the effectiveness of antiretroviral treatment."
Ref: J Acquir Immune Defic Syndr 1999;22:146-154. Source: Reuters Health
Muscle loss is a common problem in people living with HIV/AIDS. When a person's muscle mass decreases significantly, the term wasting is often applied. Both research and clinical experience have shown that people who experience wasting have a lower survival rate than those who are able to maintain their body weight. To help prevent and treat wasting, many people take nutritional supplements. One such supplement, glutamine, has recently been studied in a clinical trial in combination with antioxidants. The results of the study appear in the November issue of Nutrition.
Twenty-six patients with AIDS-related wasting received either a placebo or 40 grams of glutamine per day in combination with antioxidants. After 12 weeks, the group treated with the glutamine-antioxidant combination gained on average 2.2 kilograms, compared to 0.3 kg in the placebo group. The researchers also noted "minimal changes in fat mass and extracellular water in both groups." In other words, the subjects receiving glutamine primarily gained weight in the form of lean body mass.
In light of these findings, the researchers suggest that combining glutamine-antioxidant supplementation with nutritional counselling may provide an effective and low-cost approach to treating AIDS-related wasting.
Ref: Nutrition 1999;15:860-864. Source: "From Community AIDS Treatment Information Exchange (CATIE).
For more information visit CATIE's Information Network at http://www.catie.ca"
|
Glutamine supplementation has also been shown to influence growth hormone secretion and to have positive effects on intestinal permeability. As a dietary supplement it is readily available and commonly used in doses ranging from 5 to 50 grams per day. Oral dosing leads to rapid absorption and the elevation of plasma glutamine concentrations. |
This week physicians and researchers in the U.S. received a stronger warning from Bristol-Myers Squibb about the risk of pancreatitis in patients taking ddI (VidexTM)--a risk which may be increased if they are also taking d4T, with or without hydroxyurea (HydreaTM). ddI has been known to cause pancreatitis in some patients since before the drug was approved in 1991.
The new warning follows four deaths from pancreatitis in recent clinical trials. All four of these patients had a CD4 count greater than 500, and a viral load less than 200 copies. All four were also taking d4T; and two of the four were in a 68-patient study arm which included ddI, d4T, and hydroxyurea (600 mg BID). Three of the four who died had known risk factors for pancreatitis before they started the treatment.
If pancreatitis occurs it is important to stop the drugs and get medical attention immediately. The October 1999 "patient package insert" for ddI includes the following language to help those taking the drug recognize the symptoms (bold in original):
"Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas. It may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let you doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition occurs more often in patients who have had it previously. It is also more likely in people with advanced HIV disease, but can occur at any disease stage. It may be more common in patients with kidney problems. If you develop pancreatitis, your doctor will tell you to stop taking VIDEX."
In addition, a stronger "black box warning" is being included in the new labelling (package insert) for ddI, which has now been approved in a new formulation allowing once-daily dosing.
The letter to researchers includes the following "Patient Management" section:
"The clinical outcome of pancreatitis may be improved by early identification of the clinical and laboratory signs and symptoms of pancreatitis (abdominal pain, nausea, vomiting, elevated serum amylase and lipase levels) and prompt initiation of appropriate supportive care, including stopping all oral intake.
"Didanosine, stavudine and hydroxyurea should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine and/or hydroxyurea after a diagnosis of confirmed pancreatitis should be undertaken with caution. Didanosine should be permanently discontinued in patients with confirmed pancreatitis.
"As part of the informed consent process in new or ongoing trials, patients must be provided with written information about study drugs and their potential complications. Investigators may choose to provide subjects with the patient information leaflet for drugs administered, if available. A full informed consent process will assure that patients have the requisite information for other health care providers (e.g. emergency room personnel), should early signs of toxicity occur.
"The didanosine package insert warns that individuals with risk factors for pancreatitis should use didanosine with extreme caution and only if clearly indicated.
"Some of the known risk factors for pancreatitis include:
Source: AIDS TREATMENT NEWS #331, November 19, 1999 http://www.aegis.com/pubs/atn/1999/ATN33101.html Subscription and Editorial Office, P.O. Box 411256, San Francisco, CA 94141, TEL: 800/TREAT-1-2; 415/255-0588; FAX: 415/255-4659 aidsnews@aidsnews.org http://www.aidsnews.org
Preliminary findings suggest that combination antiretroviral therapy administered to pregnant women with advanced HIV disease can decrease the risk of vertical transmission without any major infant toxicity, according to New York-based physicians.
Dr. Joseph P. McGowan and associates report the finding from a 2-year retrospective study that included a review of the records of all HIV-infected pregnant women treated with combination antiretroviral therapy and who delivered at the Bronx-Lebanon Hospital Center.
Of the 30 women in the study, 13 received a protease inhibitor-containing regimen. Treatment was administered during the first trimester to 14 women. Overall, the subjects received antiretroviral therapy for a median of 24 weeks of pregnancy.
At baseline, the women's median CD4 count was 285 cells/µL, most were antiretroviral-experienced (67%), more than half (53%) had progressed to AIDS, and many (37%) were illicit drug users.
Over the course of gestation, close to half (47%) were non-adherent to antiretroviral therapy and 33% changed medications.
Nevertheless, most (24 women) "...had a successful viral load and/or CD4 response," Dr. McGowan's group reports in the November issue of Obstetrics and Gynaecology. And at 4 months postpartum, no cases of HIV infection were detected in any of the infants.
"The median...delivery gestation was 39 (32-42) weeks, and the median...birth weight was 2,892 (1,430-3,863) g," they write. "Adverse outcomes included 1 stillbirth; 1 case of microcephaly; and 5 infants less than 2500 g, 2 of which were under 36 weeks gestation."
However, median birth weight did not appear to be associated with protease inhibitor exposure. In addition, "...none of the live infants...had major birth defects, and there was no gross abnormality in the stillborn foetus."
Dr. McGowan's group believes these "...findings are encouraging but not conclusive with respect to the absence of major birth defects detected through the age of 4 months." Although more aggressive antiretroviral therapy in pregnancy may be warranted, they point out that the long-term infant safety of these regimens still needs to be established by large controlled trials.
Ref: Obstet Gynecol 1999;94:641-646. Source: Reuters Health
A number of presentations at ICAAC dealt with the body composition and metabolic changes associated with HAART. However, we still have little insight into the pathogenesis of these complications, no new management strategies, and no definition.
Lactic Acidosis
Lactic acidosis is a complication that was reported ten years ago as a relatively rare but often fatal complication of nucleoside analogues, seen primarily in obese women. The pathophysiologic mechanism is not understood, but it is thought to be related to mitochondrial toxicity. Lactic acidosis usually presents with fatigue, malaise, nausea, vomiting, abdominal pain, weight loss, dyspnea, and a low serum bicarbonate level. Evaluation reveals lactic acidosis, and abdominal CT scan or liver biopsy may demonstrate hepatic steatosis. Initial reports primarily implicated AZT, but this may simply have reflected usage patterns at that time. Boxwell and Styrt presented the FDA experience with this complication [Abstract 1284]. A total of 106 cases were reported through June 30, 1998, 46 with a single NRTI and 60 with dual NRTIs. In the dual nucleoside group, the most common combination was d4T/3TC. The mean time to recognition was 255 days following initiation of NRTI therapy. Hepatic steatosis was noted in 69%, and pancreatitis in 22%. Half of the patients were women, and the mortality rate was 56%. Results with other NRTI combinations were similar, but numbers were small. This type of passive reporting of adverse drug reactions grossly underestimates the frequency of these events, and the validity of the reports is highly variable. A very different experience was reported by Maulin from France who aggressively sought this diagnosis in patients with typical symptoms [Abstract 1285]. Eleven cases of symptomatic lactic acidosis were found among 867 patients, for an incidence of 0.84%/year. These 11 patients had received antiretroviral therapy for a mean duration of 27 months. The mean CD4 count was 549 cells/mm3, and the most common symptoms were asthenia, tachycardia, dyspnea, and abdominal pain. Other investigators have noted the association with underlying liver disease; in this series five had chronic hepatitis. The mean arterial lactic acid level at baseline was 4.42 mol/L, and liver biopsies demonstrated steatosis in four of five. Ten of the eleven survived, presumably due to early diagnosis and discontinuation of NRTI treatment. The authors suggested a more aggressive measurement of serum lactate levels when patients develop typical symptoms, since early discontinuation of NRTIs may be associated with a much better prognosis.
Fat Redistribution and Metabolic Complications of HAART
Three long-term complications of antiretroviral therapy are now well-recognized: insulin resistance, hyperlipidaemia, and fat redistribution. There is little agreement regarding the frequency of these complications (reflecting at least, in part, the lack of consensus definitions); there is no confirmed pathophysiologic mechanism; there are conflicting data regarding whether these are three independent processes or are interrelated; and there is little guidance in management strategies beyond the standard recommendations for managing diabetes and hyperlipidaemia. The 39th ICAAC added little new insight to this rather confused area, but there were some papers that nudged the field forward.
The incidence of hyperlipidaemia continues to show substantial variation. Virtually all authorities in the field agreed that hyperlipidaemia is a result of HAART, but the frequency of this complication with various PI-containing regimens is highly variable. The incidence in various papers was from 2.4% among recipients of IDV/ZDV/3TC in DuPont Study 006 [Abstract 1304] compared to 89% among recipients of d4T/ddI/PI [Abstract 1302]. This difference undoubtedly reflects the lack of a consensus definition, the duration of treatment at the time of analysis, the specific agents used, and the method of obtaining data. The last is particularly important, since the former study used passively collected information from a clinical trial that did not specifically address this issue, while the latter utilized far more aggressive case detection with body composition measurements using anthropometrics and bioelectric impedance. With regard to differences between agents, G. M. Moyle measured blood lipid levels in 38 patients treated for an average of 6.7 months with soft-gel saquinavir (Fortovase) [Abstract 1292]. He found that 8% (three patients) had cholesterol levels above the threshold for therapy according to the National Cholesterol Education Program, and 21% (eight) had triglyceride levels above the NCEP threshold as well. He concluded that saquinavir may cause fewer metabolic abnormalities, since it has the lowest affinity for cytochrome P450 isozymes.
Romeu also addressed the relative risk for different PIs by blood lipid measurements in 454 patients receiving PI containing regimens [Abstract 1293]. Elevated cholesterol levels were noted among all patients, with increasing frequency by duration of therapy: 26% at 12 months, 51% at 24 months, and 83% at 36 months. Similar changes were noted with sequential measurements of fasting triglycerides. To my knowledge, this is the first report that demonstrates substantial increases in lipid levels with sequential measurements after several months of treatment. With regard to specific agents, cholesterol and triglyceride levels were substantially higher among recipients of ritonavir.
This issue was also addressed in a study of salvage therapy with RTV/IDV reported by Youle [Abstract 1290]. Participants had received a PI-containing regimen prior to this combination. After the switch, there was an increase in cholesterol levels and triglyceride levels in 93% and 89% of participants, respectively. The degree of increase was substantially greater among patients who received RTV at a dose of 400 mg twice daily compared to those receiving 100 mg twice daily. The authors concluded that switching PI-containing regimens to RTV/IDV led to increases in serum lipids and that this change was directly related to the dose of ritonavir.
In a report from the HOPS by D. Ward and colleagues, 1,077 patients in eight clinics participated in face-to-face surveys to determine self-perception of fat redistribution [Abstract 1298]. Among the 529 (49%) who reported changes, 62% reported central obesity, 54% had thinning of the extremities, 47% reported fat loss over hips or buttocks, 38% had "sunken cheeks," 20% had facial structure changes, and 21% had a buffalo hump. The patients were then stratified into four categories based on the degree of fat redistribution. These groups were then analysed for lipids and glucose (random sampling). The results are shown below:
| Severity of Fat Redistribution |
None (n=548) |
Mild (n=325) |
Moderate (n=138) |
Severe (n=66) |
|
Cholesterol (median) | 192 | 203 | 206 | 212 |
|
Triglyceride (median) | 186 | 236 | 260 | 312 |
|
Glucose intolerance | 5% | 6% | 9% | 17% |
Ref: All abstract numbers refer to the 39th ICAAC, September 26-29 1999, San Francisco, USA. Source: http://www.hopkins-aids.edu/
|
HIV / HCV COINFECTION
|
The leading cause of death in HIV-infected patients is end-stage liver disease secondary to hepatitis C, at least at 1 Boston, Mass, hospital. Dr. Barbara H. McGovern of Tufts University School of Medicine presented the new data to participants at the 37th annual meeting of the Infectious Diseases Society of America in Philadelphia.
Dr. McGovern's group compared the medical records of HIV-infected patients who died in 1991 with those of patients who died between May 1998 and April 1999.
Of the 27 patients who died in 1991, they found that 4 deaths were associated with end-stage liver disease. By contrast, 11 of the 22 patients who died between 1998 and 1999 died of liver end-stage disease. Another 2, who died of other causes, also had end-stage liver disease.
This is a "very striking" finding, Dr. McGovern told Reuters Health. "And I think that this is a direct consequence of hepatitis C."
"Most of the patients in our patient population...are IV [intravenous] drug users," she continued. HIV and HCV share common routes of transmission, and previous epidemiologic studies have indicated that "...the prevalence of HCV among IV drug users ranges from 60% to 90%."
"We strongly suspect that most of the people were infected with HCV," she continued. And in fact "...the majority of patients that we did test were positive for HCV." In the 1998-1999 cohort, 15 of the 16 patients tested for HCV were positive.
"This brings home the fact that we need to evaluate both diseases in our patients," she pointed out. "Patients with HIV need HCV testing. And if patients are diagnosed with HCV, they need further evaluation, and also need to be told to abstain from drinking alcohol." If they test negative for HCV, they need to be counselled on how to prevent it.
Another important factor is that "...HCV infection in the setting of underlying HIV progresses much more rapidly from chronic active hepatitis to cirrhosis."
Starting next year, Dr. McGovern's group will be participating in a multicentre trial in which their dually infected patients will be treated with pegylated interferon with or without ribavirin. These studies will be "very important" in terms of establishing the safety and efficacy of these agents in patients with coinfection.
Source: Reuters Health
A very interesting study regarding treatment of patients co-infected with HIV and HCV (hepatitis C virus) was presented at the 7th European Conference on Clinical Aspects and Treatment of HIV Infection. The results indicated that HAART (highly active antiretroviral therapy) that included a PI drug for HIV infection was significantly associated with a decreased rate of liver fibrosis, if the patient also had hepatitis C. The lead author was Marie Bochet, MD from the Pitie-Salpetriere Hospital in Paris, France.
A total of 162 (26% women) consecutive patients co-infected with HIV and HCV (hepatitis C virus) participated in this retrospective study. A liver biopsy was performed for all patients. At the time of biopsy, the mean duration of HCV infection was 14 years. The mean CD4 count was 327 cells per microlitre, and the mean HIV RNA viral load was 17,823 copies per millilitre. (HIV viral load data were available only for 49% of patients.) HCV viral loads were not reported. Among the participants, 26% drank more than 50 grams of alcohol daily (associated with a higher liver disease progression). Protease inhibitor-based therapy was taken for greater than 12 months in 30% of the participants.
The rate of liver disease progression was calculated using the formula discussed by Poynard and colleagues in 1997. The fibrosis progression rate (FPR) was defined as the ratio between the fibrosis stage on biopsy (using the standardized METAVIR scoring system) and the duration of hepatitis C viral infection. A high FPR was defined as greater than 0.2 fibrosis units per year, while a low FPR was defined as less than 0.2 fibrosis units per year. (A high FPR would lead to liver cirrhosis in less than 20 years after HCV infection, according to Dr. Bouchet.) A high FPR was present in 28% of the patients, while a low FPR was present in 72%.
The results showed that when compared to those with a low FPR, those with a high FPR were significantly more likely to: (1) be older at the time of initial HCV infection; (2) include those who drank more than 50 grams of alcohol daily; (3) have a CD4 count less than 200 cells per microlitre; and (4) be treated with a PI drug for their HIV infection. Those who were taking a PI drug were infected with HCV significantly longer (17 years) than those who were not taking a PI drug (14 years). Also, those who were taking a PI drug had a significantly lower HIV viral load (12,154 copies per millilitre) than those not taking a PI drug (22,332 copies per millilitre). However, there were no significant differences in either the CD4 counts or the amount of daily alcohol consumed between those who were and were not taking a PI drug.
In the final statistical analysis ("logistic regression analysis"), there were only two factors that were associated with a high FPR when compared to those with a low FPR. Those factors were a CD4 count less than 200 cells per microlitre (15-fold increased odds of having a high FPR) and no previous treatment with a PI drug (3-fold increased odds of having a high FPR). The authors concluded that, "The use of (a) protease inhibitor (drug) in anti-HIV therapy is associated with a low fibrosis progression rate in HIV-HCV co-infected patients."
There are a few limitations to the study. First, this was a retrospective analysis, not a prospective study. Second, there was only one biopsy reported (and presumed to be performed) for each patient. This represents a single "picture snapshot." Comparing two different biopsies over time would represent a more definitive way to determine the true effect of a therapeutic intervention. The fibrosis progression rate was only a calculation based upon the best estimate of the duration of HCV infection. Lastly, even though HCV RNA viral loads do not correlate well with liver biopsy results, measuring those loads and incorporating them into the statistical analysis may have led to different conclusions. Nonetheless, the analysis is an interesting one. One potential conclusion would be that in HIV/HCV co-infected patients, taking a PI drug as a part of HAART may revert the rate of liver disease progression to one similar to that which occurs with HCV infection alone. However, if that were true, specific therapy for hepatitis C would still be indicated if the standard criteria were present. Those criteria would include a detectable HCV viral load and a specifically abnormal liver biopsy. Similar studies with a greater number of patients would be necessary before the conclusions could be generalized. Ref: Bochet M and others. Anti-protease inhibitor therapy decreases the liver fibrosis progression rate in HIV-HCV coinfected patients. Abstract and oral presentation 248 at the 7th European Conference on Clinical Aspects and Treatment of HIV Infection. Lisbon, Portugal; October 23-27, 1999.
Source: http://www.hivandhepatitis.com/
Douglas T. Dieterich, MD, from New York University School of Medicine, discussed the topic of co-infection with hepatitis C virus (HCV) and HIV at the 37th annual meeting of the Infectious Diseases Society of America (IDSA), November 18-21, 1999, in Philadelphia, PE. Dr. Dieterich presented recent findings from the CHORUS database that includes 4,524 HIV positive patients followed since August of 1997. The median age of participants was 39 years old. During the 24 months prior to the current analysis, there were 135 deaths. Those findings translated into the following life expectancy results: an HIV positive person who has responded to HAART (highly active antiretroviral therapy) with a CD4 count greater than 200 cells per microlitre has a projected survival of 32 years. US life tables of an HIV-negative person 39 years of age indicate a projected survival of 36 years. Those two projections are quite similar.
Dr. Dieterich also previewed some data that will be presented later this week at the IDSA meeting. Those results reveal an increasing rate of liver-related deaths among HIV/HCV co-infected patients who have stable HIV disease resulting from HAART. When these factors are considered together, Dr. Dieterich stated that there is no reason not to treat chronic hepatitis C in HIV/HCV co-infected patients with stable HIV disease from HAART.
Dr. Dieterich also previewed an IDSA presentation regarding treatment of chronic hepatitis C in patients who are co-infected with HIV. The report includes some of his patients and some patients from Johns Hopkins University School of Medicine. A total of 37 patients (24% women) co-infected with HIV/HCV were enrolled in a prospective, non-randomised treatment cohort. 84% were taking HAART. Among them, 39% were taking Retrovir (zidovudine, AZT), while 48% were taking Zerit (stavudine, d4T). (In the past, there had been some concern that combining ribavirin with either Retrovir or Zerit might lead to antagonistic or canceled effects.) Those patients taking HAART had stable HIV disease. The median baseline CD4 count was 343 cells per microlitre, while the median baseline HIV RNA viral load was less than 400 copies per millilitre. The baseline HCV RNA viral loads were not stated.
A total of 27 patients have completed 12 weeks of therapy with test results available. Among those 27, 59% took standard dosing of alfa * interferon (Intron A, Roferon, Wellferon) plus Rebetol (ribavirin), while the other 41% took only alfa interferon. The interim 12-week analysis showed that 50% of the interferon plus ribavirin arm achieved HCV RNA viral load undetectability (limit not stated). Only 9% of those in the interferon arm alone achieved undetectability. HIV RNA viral loads did not change significantly. Dr. Dieterich indicated that more information regarding these patients would be available at the poster presentation later this week. That information will include adverse events, discontinuation rates, and correlations of HCV viral response. Nonetheless, in this small group of patients, the results suggest that treating co-infected patients is possible, with good results in the very short term.
* Note that all generic versions use the spelling 'alfa' and not 'alpha.'
Ref: Dieterich DT. Hepatitis C and HIV. . "Hepatitis for the New Millennium," a Satellite Symposium at the 37th Annual Meeting of the Infectious Diseases Society of America (IDSA). November 18-21, 1999; Philadelphia, Pennsylvania. Source: http://www.hivandhepatitis.com/
|
PATHOGENESIS
|
Following evaluation of 12 HIV-infected patients who failed various drug combination regimens, Spanish investigators conclude that "...HIV-1 can acquire, independently of its genetic background, resistance to all available anti-HIV-1 drugs." Moreover, mutated virus generates high viral loads.
Dr. Marta Cabana and colleagues at Hospital Universitari Germans Trias i Pujol in Badalona longitudinally evaluated plasma samples from 12 patients who experienced clinical failure to various antiretroviral regimens.
"Complex mutational patterns in the reverse transcriptase gene were observed," they report in the December issue of the Journal of Medical Virology. "In particular, combinations of AZT (41L, 67N, 70R, 210W, and 219Q/E) and 3TC (184M) were seen in 10 patients."
Dr. Cabana's group also found multiple protease-selected mutations in all of the patients, who each harboured an average of 6 substitutions.
Detectable genotypic resistance accompanied virologic failure in most patients. "Furthermore, most patients exhibited genotypic resistance to almost all available anti-HIV-1 drugs," they write.
At follow-up most patients had high viral loads. This suggests that "...the replication of these multidrug resistant viruses are not severely compromised.
Dr. Cabana's group believes that these findings "...highlight the dangers of selecting suboptimal sequential antiretroviral therapies for HIV-1-infected persons." The data also suggest that resistance testing, especially in heavily drug-experienced patients, appears to be warranted.
Ref: J Med Virol 1999;59:480-490. Source: Reuters Health
Although data on virologic, immunologic, and clinical status can all be used to establish risk of HIV disease progression in infants, viral load remains predictive of progression, "...even after adjusting for immunologic and clinical status," according to a multicentre group.
Dr. Leslie A. Kalish of the New England Research Institutes in Watertown, Mass, and members of the Women and Infants Transmission Study group evaluated 165 HIV-1-infected children.
All of the children in this cohort were prospectively followed from birth. Between the ages of 6 and 24 months, risk factors for disease progression, including HIV-1 RNA load, CD4 T-cell level, and clinical status, were assessed at fixed ages and as temporal variables.
Overall, the researchers found that the "...virologic, immunologic, and clinical status over time each provide independent information regarding HIV-1 disease progression risk in children." However, even after they adjusted for "...immunologic and clinical stage, virus load provided additional information regarding short- and long-term risk at all ages studied," they report in the November issue of the Journal of Infectious Diseases.
Dr. Kalish's team also found that the children's immunologic stage was a "...stronger independent predictor of short-term risk than long-term risk." This implies that "...CD4 T-cell level reflects "current" disease stage more than it predicts future disease."
They also found that "...reaching CDC clinical class B at an early age is an independent marker of future progression," and that "...class C versus classes N/A/B becomes more important as the patient ages."
Ref: J Infect Dis 1999;180:1514-1520. Source: Reuters Health
|
REGULATORY AFFAIRS
|
The European pharmaceutical licensing authority's scientific advisory board has rejected licensing applications for the Glaxo-Wellcome protease inhibitor amprenavir and the Pharmacia & Upjohn NNRTI delavirdine.
Amprenavir will be reviewed again in six months time after the results of salvage therapy studies are available. The committee was not prepared to license amprenavir for first-line therapy because of its poor performance when tested head to head against indinavir in treatment-naive individuals, and because insufficient data is available on its use as a second-line protease inhibitor in people who have failed currently licensed PIs.
Delavirdine was withdrawn from consideration by its manufacturer Pharmacia & Upjohn after members of the CPMP made it clear that the company had provided them with insufficient data about delavirdine's interactions with protease inhibitors. The company was also unable to prove that delavirdine, a three times daily drug, offers any added benefits compared with the NNRTIs already licensed, efavirenz and nevirapine, in terms of side effect profile, efficacy or dosing schedule.
The delay means that amprenavir is unlikely to be launched in Europe until the last quarter of 2000, more than a year and half after its US launch. The decisions also signal that European licensing authorities intend to take a much tougher line on drugs which are not products in a new class, and that future protease inhibitors, NNRTIs and NRTIs will have to demonstrate that they offer valuable additions to the range of drugs already licensed.
Expanded access arrangements for delavirdine are now unclear, because Pharmacia & Upjohn has sold marketing rights to Agouron/Warner-Lambert.
Source: http://www.aidsmap.com/
Agouron Pharmaceuticals, Inc. today announced that the Food and Drug Administration (FDA) has approved twice daily dosing (BID) of nelfinavir mesylate (ViraceptTM) for the treatment of HIV infection. Approval supports 1250mg BID dosing of nelfinavir based on data that showed comparable anti-HIV effects and safety to the previously approved 750mg three times daily dosing (TID).
The clearance was based principally on interim results from a pivotal phase III trial involving more than 500 patients that showed similar decreases in plasma HIV RNA and increases in CD4+ T cell counts between 1250mg BID and 750mg TID dosing of nelfinavir, and a similar safety profile, when used in combination with standard doses of d4T and 3TC.
Nelfinavir is generally well-tolerated when taken 1250 mg BID or 750 mg TID. In study 542, diarrhoea of moderate or greater intensity occurred in 14% to 18% of patients receiving nelfinavir 1250 mg BID or 750 mg TID with stavudine or lamivudine. New onset or exacerbation of diabetes mellitus and hyperglycaemia, changes in the distribution of body fat, and increased bleeding in patients with haemophilia types A and B have been reported with protease inhibitors including nelfinavir.
Source: Company press release.
Abbott Laboratories announced that it has received marketing authorization from the European Commission for ritonavir (Norvir(r)) soft capsules. Ritonavir is a protease inhibitor indicated in combination with other antiretroviral medications for the treatment of HIV infection.
The approval of Norvir capsules follows intense reformulation work at Abbott after an announcement in July 1998 that a new crystalline structure of ritonavir, that affected how the semi-solid capsule dissolved, would interrupt the production of Norvir semi-solid capsules. The soft capsule has undergone a number of tests to ensure its stability. Ritonavir oral solution has allowed patients to continue therapy during the period of time when semi-solid capsules were not available. New ritonavir soft capsules will be available immediately in countries where pricing approval is not required.
Norvir soft capsules require refrigerated storage between 2¼C and 8¼C until dispensed to patients. Refrigeration by patients is recommended, but not required, if used within 30 days and stored below 25¼C.
|
DRUG - DRUG INTERACTIONS
|
Some males who experience problems getting or maintaining an erection can use the drug Viagra (sildenafil) for relief. Because Viagra and protease inhibitors are processed by the liver, some doctors are concerned that they may interact, causing side effects. Doctors in Ireland and England conducted a small study to try to understand how Viagra and indinavir interact. They also performed laboratory studies with liver cells and protease inhibitors to see how the liver dealt with this drug combination. According to their results, indinavir raised levels of Viagra. Based on these results, the researchers make suggestions concerning how much Viagra indinavir users should take and how often they should take it.
Researchers recruited six HIV-positive males with an average weight of 66 kg and 333 CD4+ cells. All subjects were taking two nucleoside analogues (nukes) and indinavir. Subjects remained in hospital overnight and took their anti-HIV medications on an empty stomach. Nurses took blood samples for analysis on a regular basis. On the second day, subjects took 25 mg of Viagra with their morning dose of anti-HIV medication.
Taking 25 mg of Viagra with indinavir boosted Viagra levels in the blood four times higher than they otherwise would reach. Indeed, the interaction between the two drugs had the same effect as taking 100 mg of Viagra without indinavir. All subjects reported headache, flushing and other adverse effects associated with Viagra. The effects lasted for up to three days after subjects took the drug.
Results from the experiments with liver cells suggest that indinavir impairs the liver's ability to break down Viagra, and that probably explains the increase in Viagra levels in the study subjects.
The research team suggests that people using indinavir who also wish to take Viagra may want to start with a reduced dose of Viagra - 12.5 mg. This reduced starting dose may minimize side effects. As well, since it's possible that Viagra levels could build up when taken with indinavir, the researchers suggest that it may be appropriate for people taking indinavir to use Viagra no more than once or twice a week.
Ref: Merry C, Barry MG, Ryan M, et al. Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. AIDS 1999;13:F101-F107. Source: CATIE News.
|
IMMUNOTHERAPY
|
The majority of patients with AIDS respond to HAART (highly active antiretroviral therapy) with at least an initial decrease in HIV RNA viral load. However, a subset of these patients with later stage disease does not significantly increase their CD4 cell counts. In the first randomised trial to evaluate the addition of Proleukin injections to HAART, such patients did sustain a significant increase in their CD4 counts. The interim 24-week data were presented at a Late Breaker presentation at the 7th European Conference on Clinical Aspects and Treatment of HIV Infection. The lead author was Christine Katlama, MD from the Pitie-Salpetriere Hospital in Paris, France.
Seventy patients with AIDS were enrolled in ANRS 082. Entry criteria included the following. All patients must have had: (1) HAART-induced reduction in HIV viral load to less than 1,000 copies per millilitre for at least six months and (2) CD4 counts that were persistently less than 200 cells per microlitre during the same period.
Patients were randomised to receive continued HAART plus Proleukin or continued HAART plus placebo. The dose of Proleukin during the 24 weeks was 4 1/2 million international units (MIU) injected subcutaneously (under the skin) twice daily, five days per week, every six weeks. Therefore, the Proleukin arm had four cycles of Proleukin injections at the 24-week interim analysis.
A total of 34 patients were randomised to the Proleukin arm, while 36 patients were randomised to the placebo arm. The median baseline counts were 149 and 138 cells per microlitre for the Proleukin and placebo arms, respectively. Baseline viral loads were not stated. However, all patients had a baseline viral load less than 1,000 copies per millilitre.
The interim results after 24 weeks were as follows. The median increases in the CD4 counts were 65 cells per microlitre for the Proleukin arm and 18 cells per microlitre in the placebo arm. The results were highly statistically significant. However, there was considerable overlap between the two groups in that evaluation. Also, the number and percentage of patients who had a CD4 count increase of 50 cells per microlitre or greater was significantly higher in the Proleukin arm than the placebo arm. The number (percentage) with such an increase was 25 (73%) in the Proleukin arm and 8 (22%) in the placebo arm. The CD4 cell increases in the Proleukin arm included a significant proportion of "na•ve" cells. Na•ve lymphocytes are ones that are able to respond to new antigens (infecting organisms). Also, the Proleukin arm had a significantly greater increase in their lymphoproliferative responses to CMV (cytomegalovirus), a sight-threatening AIDS opportunistic infection than the placebo arm.
Seven patients in the Proleukin arm and one patient in the placebo arm had a transient increase in their viral loads to greater than 1,000 copies per millilitre. At the 24-week time point, four patients in the Proleukin arm had a viral load between 1,000 and 3,000 copies per millilitre.
There were no unexpected adverse reactions to Proleukin. Common side effects are "flu"-like symptoms. In the Proleukin arm, one patient stopped therapy and five patients required a reduction in dosage.
The authors conclude that Proleukin "significantly increases the number of CD4 cells (increase of a median 65 cells per microlitre) over 24 weeks in patients with persistent[ly] low CD4 lymphocytes despite HAART. Tolerance was quite acceptable." These patients will be followed for a longer period of time, up to at least 80 weeks. Starting at 24 weeks, the placebo and Proleukin arms will both receive Proleukin at a dose of 9 MIU daily, five days per week every eight weeks. This is the same daily dose as the original Proleukin arm. The cycles will have a longer interval of eight weeks, compared to the initial interval of four weeks. This extension of the study will allow for more detailed analysis about dosing of Proleukin.
Even though this is a small study, it would appear that ultimately, Proleukin will have a significant role to play, in addition to HAART, in the treatment of HIV disease. Ultimately, the CD4 count is the major factor that predicts specific life threatening AIDS opportunistic infections (OIs). (However, high HIV viral loads also have been shown to be a co-factor that increases the risk of certain OIs.) Nonetheless, the higher the CD4 count (up to a normal or near-normal range), the better the patient will be. A significant question will be at what stage of HIV infection Proleukin should be started. The more advanced HIV infection is, the less the response is to this potent immune therapy. Ref: Katlama C and others. ILSTIM (ANRS 082)-a randomised comparative open-label study of interleukin-2 (IL2) in patients with CD4<200/mm3 despite effective HAART. Late Breaker abstract and oral presentation 1205 at the 7th European Conference on Clinical Aspects and Treatment of HIV Infection. Lisbon, Portugal; October 23-27, 1999.
Source: http://www.hivandhepatitis.com/
|
This data was sufficiently important for this treatment adjunct to be recommended as an option for this patient group in the recent French Guidelines. Should IL-2 now be routinely offered to all those with "stuck" CD4 response? Stimulation of immunity to OI's and the possibility of reducing prophylaxis would yield obvious benefits. IL-2 is available both "off-label" and through a named patient programme. |
ATP Symposium VHIV-2 |
Friday January 14th 2000
Florence Nightingale Lecture Theatre, St Thomas' Hospital, London SE1 7EH
The Medical Research Council (MRC) and the AIDS Treatment Project (ATP) are jointly sponsoring a symposium on Human Immunodeficiency Virus type 2(HIV-2). The meeting will focus on biological differences between HIV-2 and HIV-1, the problems of monitoring disease progression, anti-retroviral treatment and management of HIV-2 during pregnancy.
Since its discovery in 1986, HIV-2 has been a leading cause of HIV-related disease in parts of West Africa. Although less pathogenic than HIV-1, research into HIV-2 has raised specific issues of wide-ranging interest to scientists and clinicians. For example, in contrast to HIV-1, the majority of patients infected with HIV-2 generally live asymptomatically for many years and only a small proportion rapidly progress to AIDS and death.
This symposium will address current issues in HIV-2 research and clinical management:
| HIV vaccines? |
|
Increasing awareness of HIV-2 disease in Europe has highlighted the difficulties in monitoring HIV-2 infection and the problems of treating a viral infection where the clinical outcome is unclear. The different susceptibility of HIV-2 to certain anti-retroviral drugs also has implications for the choice of optimal therapy.
The meeting will bring together scientists and clinicians working in the field of HIV-2 from Europe, Africa and the UK in order to stimulate discussion around the scientific and clinical issues, and to identify areas for future collaborative research. The discussions will also address issues of best practice in the management of this infection.
We are looking forward to an exciting and stimulating meeting. Early booking is recommended, as places are limited. Pleasecontact the ATP office for a registration pack.
Registration forms to: Dr Nicola Smith, 0208 846 1578 (t), 0208 846 7582 (f) West London Centre of Sexual Health, Charing Cross Hospital, London W6 8RF. Further information: Dr Nicola Smith, as above Dr Judy Breuer 0207 377 7141(t), 0207 377 5784 (f) j.breuer.@mds.qmw.ac.uk