ISSUE 72 - Conference Report Special
Editor Paul Blanchard
Medical Consultant
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June 23 - 26, San Diego, CA. |
Felipe Garcia, with the Hospital Clinic at the University of Barcelona, reported follow-up data on this group of patients first reported on at the '99 Human Retroviral Conference in February, which was reviewed in the April NATAP Reports newsletter available on the NATAP web site. Interrupting and stopping therapy has become an interesting therapeutic approach because of the difficulties in maintaining long-term adherence to HAART, and because eradication from HAART appears elusive. With the waning of hope for eradication, there has been interest that an immune system response to HIV could be elicited by interrupting therapy, which might lead to control of HIV by the immune system.
Garcia reported data after two therapy interruptions. Ten patients were initially included in the study with CD4 counts >500. They started therapy with d4T+3TC and either ritonavir or indinavir. After 1 year of treatment patients had a plasma viral load <20 copies/ml, volunteered to stop therapy and had been below 20 copies/ml for at least 8 months before stopping all antiretrovirals.
The study methods are as follows. Patients initially stopped therapy after 1 year of therapy (day 0) when viral load was <20 copies and re-started therapy after 4 weeks if VL >200 copies/ml. They received treatment for 6 more months. Then if viral load was <20 copies/ml the patient was offered to stop therapy again (week 28). Treatment was re-introduced (week 32) after 4 weeks if viral load was >200 copies/ml and if viral load did not drop spontaneously (without HAART). The follow-up is just beyond the 32-week point. They are planning to give patients 6 months more therapy followed by a third interruption.
Measurements of plasma and CSF and lymphatic tissue HIV RNA viral load, CD4 lymphocyte proliferative responses to mitogens and specific antigens (including HIV-1 Ag), and lymphocyte immunophenotyping were performed weekly. Genotypic resistance was assessed after the rebounds of viral load off therapy and at baseline.
Just prior to the first stop (week 0), plasma viral load was <20 copies in all cases and below 5 copies/ml in 7/10 patients. CSF viral load was <20 copies/ml in all patients. Among the 6 patients with accessible tonsils, tonsillar tissue VL was <40 copies/ml of tissue in 5 and 485 copies/mg in the other patient. So this was a well suppressed group of patients. Nine patients reached the time point of the second stop. At week 28 (2nd stop), plasma VL was <20 copies/ml in all cases and below 5 copies/ml in 7/9.
A rebound in plasma VL occurred in all cases, with a mean doubling time (DT) of 2.32 days in the first stop and 3.38 days in the second stop. Doubling time is the amount of time for viral load to increase 100%. In 2 patients the DT increased from 2.48 to 8.68 and from 3.85 to 8.65 days, respectively. DT did not change in 7/9 patients who completed both stops. Four patients' viral load rose higher than their baseline before starting therapy, both at the first and second stop.
After the first stop, one month after re-starting therapy VL dropped below 20 copies/ml again in all patients and remained <20 copies/ml after 6 months until the 2nd stop.
However, after the second stop 4 patients' viral load rebounded to similar levels of their baseline level but then dropped spontaneously (without therapy). The drops ranged from -0.80 log to -2.09 log. A proliferative p24 response was detected in 2 of these 4 only after the second stop.
Virus RNA samples after both stops did not have any detectable RT or protease mutations known to be associated with resistance to RT inhibitors or protease inhibitors. They used the Visible Genetics System for genotyping.
At the beginning of the first stop, the patients' CD4s, naïve CD4s and CD8s decreased. There was an increase in CD38+CD8 cells and of both memory CD4s and memory CD8s. There was no proliferative p24 Ag response detected in any patients. Garcia reported that 6 months after restarting therapy patients regained these losses in the immune system back to where they were prior to the stop. After the second stop CD4s decreased but CD38+ CD8 cells did not change and the naïve and memory cells did not change. However, a proliferative p24 response was detected in 2/10 patients. Again, these 2 were 2 of the 4 patients whose viral load dropped spontaneously after the second stop.
In summary, Garcia concluded by saying that in a cohort of well controlled (virologically) asymptomatic patients in very early stages of disease after 1 year of HAART:
Garcia characterised interruption as being relatively safe with lack of resistance, quick virological response after re-introducing HAART, and complete recovery of immune deterioration after a further 6 months of HAART (lesser immune deterioration after second stop).
Source: Jules Leven, NATAP Reports. www.natap.org
Ref: Garcia F, Plana M, Cruceta A et al. Dynamics of viral load rebound and immunological changes in two consecutive interruptions of antiretroviral therapy. Abstract 165. Antiviral Ther 1999;4(suppl 1):6-7.
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A 3 fold increase in doubling time on the 2nd treatment interruption represents viral load rebound at 8 days versus 2 days on the first interruption. Although not clinically relevant in itself this does indicate that viral rebound dynamics may be affected by host immune factors. The question then remains - how many treatment interruptions might lead to a clinically useful period of viral suppression before rebound? Each treatment interruption will increase the risk of resistance during withdrawal and reintroduction as plasma levels fall or rise to inhibitory levels. This may be of most concern with long half-life drugs such as the NNRTI's, but could also be of concern with all drugs with repeated interruptions. Until this phenomenon is better defined it would clearly be inadvisable to try this strategy outside of a research setting. |
Andrew Phillips and colleagues at the Royal Free and University College Medical School in London, reported on this analysis of the Frankfurt cohort - 406 drug-naïve patients who started a HAART regimen including protease inhibitor or NNRTI therapy with 2 NRTIs. The median baseline viral load was 250,000 copies/ml (range 830-5 million). The median CD4 was 259. Using a sensitive viral load assay the median VL decline was 4.8 logs by week 48. This method permitted characterising the full VL decline, which is normally cut off by detection limits of the assays usually used. Ninety-one percent reached VL <500 copies/ml by 24 weeks. Of those who achieved a VL <500 (n=342), 69 had a viral rebound (2 consecutive values >500 copies/ml) in 344 person years of follow-up. There was a fairly low overall rate of rebound. By week 48 21% experienced a VL rebound after initial suppression below 500 copies/ml. However, the rate of VL rebound decreased as only a further 5% experienced rebound at the 96 week time-point.
Ninety-seven percent of patients who reduced their VL <500 copies/ml had at least 1 HIV-RNA value <50 copies/ml. Statistical analysis (Cox regression analysis) indicated that there was a significant decrease in the rate of viral rebound with increasing length of viral suppression. That is, the longer you stay undetectable the longer you are more likely to remain undetectable, if adherent. There was a rate of only 0.8 rebounds per 10 years (8 rebounds in 99 person-years; i.e. average of 1 rebound per 12.4 years) in people who had experienced VL <500 copies/ml for over 1 year.
In conclusion-- Phillips said that although we have not followed patients for more than a maximum of about 3 years this low and decreasing rate of viral rebound in patients with at least 1 year viral suppression implies that, if prolonged complete drug adherence were possible, long-term viral suppression for 10 years and more seems within the capacity of presently available regimens.
Source: Jules Leven, NATAP Reports. www.natap.org
Ref: Phillips A, Miller V, Sabin C. Low and decreasing rate of viral rebound with prolonged viral suppression on HAART: insights into the long-term impact of resistance. Abstract 166. Antiviral Ther 1999;4(suppl 1):6-7.
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Of course, decreasing rates of rebound in the 2nd or 3rd year of therapy does not preclude the increase in rates of virological failure which might follow in say the 4th, 5th and subsequent years. This is not predictable from 2 or 3 year data alone. The rate figures generated from this data tell us that in 100 patients completing one year of follow-up 8 will rebound, 92 stay suppressed. Care is needed that this is not interpreted as a 0.8% chance of rebounding over 10 years of therapy in a single patient. |
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The First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV took place in San Diego, USA, on 26-28 June 1999. It was well attended and the abstract, presentations and posters provided a broad spectrum on the lipodystrophy syndrome, with contributions from key speakers in their respective fields. The workshop was organised to review the data and to develop a consensus definition of the syndrome.
[All abstract numbers refer to Antiviral Therapy 1999; 4 (Supplement 2).]
The final sessions of the conference concerned reaching a consensus on a case definition for lipodystrophy. This was not to be cast in stone, but was a working definition to take forward.
The conference was divided into five discussion groups on fat loss, fat accumulation, lipid disturbances, glucose disturbances and miscellaneous [including cardiovascular risk]. A designated doctor, a community activist, and the leader of each group fed back the group's summary. Dr Schambelan, from San Francisco General Hospital and Dr Carr from Sydney, Australia then presented the interim working definition. Dr Schambelan stressed this was not diagnostic criteria but for clinical research purposes.
Hollow cheeks [facial], loss of buttocks, prominent [non-varical] veins. Other locations may need to be included in future.
Abdomen increase, breast enlargement, intrascapular fat pad ["buffalo hump"], lipomas in other locations, facial accumulation [neck, under jawline]. Other locations may need to be included in future.
Method of assessment would be by clinical confirmation of a patient's self report or by clinical observation alone, as opposed to patient self report alone or data from prior clinical records. There is not enough data at the present time to set quantitative criteria although including quantitative measurements will be helpful in establishing a future case definition).
Laboratory data should include the following information: fasting triglycerides >2.2 mmol, fasting cholesterol >5.0mmol (LDL and HDL measurements and the LDL/HDL ratio would be useful.), fasting glucose, insulin (calculation of glucose/insulin ratio would be helpful), c-peptide (>20).
Gender, race, age, BMI, lifestyle/family history, duration of HIV infection, past and current anti-HIV therapy.
Studies to determine diagnostic criteria should have the following specifics, as summarised by Dr Carr (these are modified according to the criteria used by the American College of Rheumatology):
There were a number of reports from patient cohort groups from Australia, USA and Europe, which found a high association between d4T and fat redistribution.
One such report was from Dr Andrew Carr, Dr David Cooper and their colleagues from Sydney, Australia [Abstract 011]. Following the hypothesis that mitochondrial toxicity of nucleoside analogues might contribute to lipodystrophy they examined their cohort for non-PI related cases.
14 nucleoside reverse transcriptase inhibitor (NRTI) patients with lipodystrophy (LD), with a mean 61 months therapy, were compared with 32 drug-naive without LD, 28 NRTI patients without LD, 44 NRTI + PI patients without LD and 102 NRTI + PI patients with LD. Dr Carr reported that the NRTI patients were on 2 NRTIs while the PI patients were on the same plus a PI. Body composition was assessed by personal questionnaire, physical exam, DEXA and abdominal CT scans, with lipid, glucose and biochemical parameters. NRTI LD syndrome was characterised by recent onset fatigue and nausea, peripheral LD (mean 6kg fat loss over 4 months), abdominal distension and elevated serum lactate (P<0.0001 for case group versus each control group).
The body fat changes in people on NRTIs were either peripheral fat loss or abdominal distension, Although physically similar, NRTI LD differed from PI LD by recent onset symptoms - nausea, fatigue and weight loss - and higher lactate and lower lipids, glucose and insulin. In a multivariate analysis, current d4T use and total NRTI duration were statistically associated with LD. In treated controls, PI duration (P<0.007) and lactic acidaemia (P<0.05) were independently associated with both LD and central obesity.
Dr Carr also reported that metabolic disturbances improved after NRTI cessation but weight gain was limited.
Dr M. John, from Royal Perth Hospital, Australia, presented information on fat loss in cohort group of 271 patients [Abstract 019]. Standardised clinical criteria were used. Time to onset of clinically apparent fat loss in patients receiving different anti-retroviral regimens was compared; percentage body fat composition as measured by DEXA in 156 patients was also compared. Fat wasting was found in 14% of PI naive patients ( P<0.001) and 51% of PI patients. Using "multivariate logistic regression" Dr John reported that shorter time to onset of fat wasting was associated with: age (P=0.0001); race (P=0.025 for whites); longer duration of dual NRTI therapy prior to HAART (P=0.013); increased cumulative time on d4T-containing HAART compared with time on ZDV (P=0.0001).
Treatment with a double NRTI regimen led to slower development of lipodystrophy compared to triple therapy including a PI. Additionally, longer cumulative times on any d4T-containing regimen were associated statistically with lower percentage subcutaneous fat in the legs.
Dr Galli and colleagues from Milan University, Italy, reported data from their cohort on NRTI associated wasting [Abstract 020]. 191 PI-naive patients taking or starting a double NRTI therapy were evaluated for fat redistribution. The analysis was performed on patients who remained on double NRTI treatment, without adding a NNRTI or PI. Of six different double NRTI combinations d4T/3TC was statistically associated with fat redistribution, with a rate of 27.1%. All NRTI combinations had a minimum rate of fat redistribution of 9%, with two of the three d4T combinations having the highest rates. The researchers concluded that fat redistribution was high also in PI-naive subjects on double NRTI combinations. As well as the combination d4T/3TC being statistically associated with fat redistribution the risk of developing fat redistribution on NRTI's was also found to be higher in women.
R. Polo and colleagues at Hospital Carlos, Madrid, also concluded that NRTIs "must have some impact" on the development of LD, with the strongest effect being shown by the d4T/ddI combination (88.2%) in contrast to the ZDV/3TC group (2.2%). 150 subjects were grouped according to the NRTI treatment received at lest six months before study entry. The three regimens were PI + (a) ZDV/3TC (n=46); (b) d4T/3TC (n=87); (c) d4T/ddI (n=17). On study entry the rates for LD were 2%, 25% and 65% respectively. After six months the rates were 2%, 52% and 88%, with group (a) maintaining the low rate and both (b) and (c) rising.
Two patients from group (c) with diagnosed LD were switched to ZDV/3TC, with the PI maintained, and followed for further six months. This switch led to significant improvements (as early as 12 weeks) in anthropometric measurements, which continued to improve at 24 weeks. The improvements included increased total body fat mass; decreased abdominal and thoracic width; and increased arm width. Triglyceride levels also improved.
Another report from Dr T. Saint-Marc, Hôpital Herriot, Lyons, France [Abstract 024], looked at the discontinuation of d4T in 14 patients with lipoatrophic lipodystrophy on stable NRTI therapy and in 15 patients on a PI containing regime. After six months a significant (P<0.05) increase in body fat was seen in both groups: abdominal and mid-thigh subcutaneous fat area increased by 41% and 40.7% in the NRTI group (P<0.01) and 27% and 47% in the PI group (P<0.01).
There were also reports where a relationship was not found between d4T and fat redistribution. A report from the French Aquitaine cohort [Abstract 018] found that of the 581 patients in this group 220 presented with LD. Of this 220, 31 were PI-naive (14%). No statistical relationship between LD and d4T was found, nor for 3TC.
A report came from the START studies in the USA [Abstract 030]. Based on their "ad hoc analysis", they found no clinically significant differences in LD between the ZDV and d4T groups. The researchers combined the d4T/3TC/indinavir group (n=100) with the d4T/ddI/indinavir group (n=102) and compared these with a ZDV/3TC/indinavir group (n=205) for LD related events. The researchers also examined only "investigator text and coded terms for all events".
Data from the HOPS (HIV Outpatient Study) cohort was presented [Abstract 014]. 1077 patients visiting eight clinics in seven US cities were interviewed and assessed during the last three months of 1998 by HOPS clinicians. Fat redistribution (loss and gain) was evaluated; the physical signs being rated as none (level A), mild (B), moderate (C) and severe (D). Time since HIV diagnosis was significantly and independently associated with the severity of LD: median years for group A-6.3; B -7.1; C -8.4; D -9.0.
In an analysis controlling for time since HIV diagnosis, the factors significantly associated with LD were: age (median: group A - 39 years; B - 42 years; C - 44 years; D - 45 years: Cochran-Mantel-Haenszel {CMH} P<. 001); lowest ever CD4% (CMH P<0.01); CD4% rebound from nadir (CMH P<0.01); and duration of therapy for only: d4T, 3TC, indinavir (CMH P<0.001) and saquinavir (CMH P<0.016). The researchers maintain that these results suggest that the causes of fat redistribution syndrome are multifactorial. The researchers also documented the types of fat redistribution that occur from all causes. In order of decreasing frequency, these are abdominal obesity; fat loss in extremities; fat loss in buttocks; sunken cheeks; fat accumulation in neck and under jaw; dorsocervical fat pad.
The authors of this report, Dr D. Ward and colleagues stressed that association does not necessarily mean causation. The time on d4T, for example, or indinavir, may be a surrogate marker for time on successful and well -tolerated anti-HIV therapy. Dr Kotler, from New York, has suggested that LD may be the result of raised CD4s and reduced viral loads due to therapy after a prolonged period of HIV infection. Dr Carr concurred that it may be HIV infection itself that is associated with LD. An additional possibility could be that some years of NRTI therapy may start the process of LD, and adding a PI could speed up the process and/or lead to more pronounced LD.
Dr Kees Brinkman, from The Netherlands, on the mitochondrial toxicity of NRTIs stated that NRTIs inhibit DNA polymerise, the only enzyme responsible for mitochondrial DNA (mtDNA) replication, leading to mtDNA depletion. He reported that the complications of NRTI drugs are due to their inhibiting this gene in mitochondria. Conditions that can develop as a result of NRTI-related toxicities include: myopathy, neuropathy, liver steatosis, bone marrow failure, pancreas failure. Also, mitochondria damage can lead to (fatal) lactic acidosis, the most serious presentation of mitochondrial toxicity, presenting with abdominal discomfort nausea and vomiting, followed by tachypnoea and rapid deterioration. The toxicity occurs after months of NRTI therapy and people who have suffered other NRTI toxicity appear to be at increased risk. Dr Brinkman reported on five patients in whom lactic acidosis on NRTI treatment appears to have been triggered by a period of metabolic stress, such as a severe infection or malnutrition and associated low intake of critical vitamins. Dr Brinkman said that vitamin supplementation with co-factor supplements like riboflavin; co-enzyme Q and L-carnitine can be beneficial. In looking at other therapeutic options, early recognition is essential and NRTIs have to be stopped immediately. Screening tests for the development of mitochondrial dysfunction are not available. Random analysis of lactate concentration and lactate/pyruvate (L/P) ratios showed higher values in persons who had NRTI related toxicity, but there are confounding factors which make these unreliable. Similarly, glucose loading resulted in an increase in L/P ratio in NRTI patients, but this test will be too laborious for routine screening. Dr Brinkman stated that to demonstrate mitochondrial failure, invasive procedures like muscle or liver biopsies are definitive but impractical for routine use.
High levels of blood lactate are more commonly seen in other conditions of hospitalised HIV+ patients according to a poster presentation by Dr Trantisiriwat, from St. Louis, Missouri. In a retrospective review of all HIV-infected patients with increased lactic levels from 1996-1998. The most common causes of lactic acid level were sepsis - 42.4% and pancreatitis -5.2%.
Dr Brinkman also proposed NRTI drug toxicity of adiposite mitochondria as a mechanism of NRTI-induced fat redistribution: that mitochondria in adipocytes may lead to tissue abnormalities, either fat cell loss or accumulation, depending on the location in the body. A poster presentation by T. N. Kakuda and colleagues, from the University of Minnesota also hypothesised that NRTIs may precipitate fat redistribution, without excluding other factors.
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OTHER NEWS
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A joint Uganda-U.S. study has found a highly effective and safe drug regimen for preventing transmission of HIV from an infected mother to her new-born that is more affordable and practical than any other examined to date. Interim results from the study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), demonstrate that a single oral dose of the antiretroviral drug nevirapine (NVP) given to an HIV-infected woman in labour and another to her baby within three days of birth reduces the transmission rate by half compared to a similar short course of ZDV. If implemented widely in developing countries, this intervention potentially could prevent some 300,000 to 400,000 new-borns per year from beginning life infected with HIV.
In an announcement from Kampala this morning, Ugandan officials hailed the finding. "This research provides real hope that we may be able to protect many of Africa's next generation from the ravages of AIDS," says Crispus Kiyonga, M.B.Ch.B., Uganda's Minister of Health. "We commend the collaborative effort of our country's scientists, led by Professor Francis Mmiro from Makerere University Faculty of Medicine, and their U.S. colleagues, led by Dr. Brooks Jackson from The Johns Hopkins University School of Medicine."
Finding affordable interventions for developing countries is key to curtailing the global AIDS epidemic. In parts of the hardest-hit area, sub-Saharan Africa, up to 30 percent of pregnant women are infected with HIV, and 25 to 35 percent of their infants will be born infected. The UNAIDS estimates that approximately 1,800 HIV-infected babies are born every day in developing countries.
Unfortunately, the standard ZDV regimen used to prevent perinatal HIV transmission is too expensive and impractical for widespread use in developing countries where many women may not receive prenatal care.
The Uganda study investigators, part of the NIAID-supported HIV Prevention Trials Network (HIVNET), opened the trial two years ago at Mulago Hospital, affiliated with Makerere University, in Kampala, Uganda. They completed enrolment last April. All women entered into the study were in their ninth month of pregnancy. None had taken antiretroviral drugs while pregnant.
The study, known as HIVNET 012, compared the safety and efficacy of two different short-course regimens of antiviral drugs administered late in pregnancy. The women were assigned at random to receive either a 200-mg dose of oral nevirapine at the onset of labour, followed by a 2-mg/kg oral dose given to their babies within three days of birth; or a 600-mg dose of ZDV at the onset of labour, and 300-mg doses every three hours thereafter during labour. The infants born to mothers in the ZDV group received 4 mg/kg given twice daily for the first week of life. Both drugs appeared to be safe and well tolerated.
Study design, data collection and analysis was provided by a team of researchers led by Dr. Thomas Fleming, a biostatistican at the Fred Hutchinson Cancer Research Center and the University of Washington School of Public Health and Community medicine in Seattle.
For the interim analysis, the study team looked at data from 618 mothers (308 receiving ZDV and 310 receiving nevirapine) and their infants. Nevirapine was markedly more effective. At 14 to 16 weeks of age, 13.1 percent of infants who received nevirapine were infected with HIV, compared with 25.1 percent of those in the ZDV group.
"In this study, the short-course nevirapine regimen resulted in a 47 percent reduction in mother-to-infant HIV transmission compared with a short course of ZDV. The implications of this study for developing countries, where 95 percent of the AIDS epidemic is occurring, are profound," says Brooks Jackson, M.D., the lead U.S. investigator on the trial.
Long-term follow-up of both the mothers and their babies remains a high priority to assess any late drug toxicities as well as long-term survival. The mothers and their children will continue to be actively followed until the babies are 18 months old. This period is critical to establish the efficacy of the intervention because even if a baby is born HIV-free, he or she may acquire the virus during breastfeeding. The data analysed so far cover only the first three months of the new-born's life. Ugandan and U.S. investigators will soon launch a follow-up study to evaluate the efficacy of nevirapine administered to the mother during labour and to the new-borns for a longer period of time.
Breastfeeding is practised widely in developing countries. Most studies indicate that the rate of HIV transmission via breastfeeding is highest in the first few months of life. No intervention has yet been shown to prevent HIV transmission through breast milk other than not breastfeeding.
The single-dose nevirapine regimen to mother and infant substantially lowers the cost barrier that has kept many countries from adopting drug strategies that prevent perinatal HIV transmission. Still, access to other health care services required to implement this regimen, such as counselling and voluntary HIV testing, are beyond available resources of many developing countries. But if further research upholds nevirapine's good safety record, the investigators say that potentially all pregnant women who live in areas of high HIV prevalence could receive the drug during labour, even in the absence of an established HIV diagnosis.
Nevirapine, developed by Boehringer Ingelheim Pharmaceuticals, is a non-nucleoside reverse transcriptase inhibitor, and is in a different class of antiviral drugs than ZDV but works against the same HIV target enzyme that is critical for the virus to infect new cells. It can be easily stored at room temperature. Besides being inexpensive and potent, nevirapine is rapidly absorbed and transferred across the placenta to the infant, and it breaks down slowly. For these reasons, it was thought that even a single dose to the mother and infant might provide enough protection to the baby during the time of exposure to HIV at birth.
The full executive summary of the HIVNET 012 study is available on the NIAID web site at:
Source: NIAID Press Release.
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This study clearly offers an alternative strategy for the reduction in risk of vertical transmission. With gathering concerns over toxicity's of NRTI's, their incorporation into DNA and risks even to the uninfected child NNRTI's may be an increasingly attractive option in the developed world as well as resource poor settings. Even with a single dose to the mother and a second to the infant concerns do, however, remain over the potential to induce resistance. The risk of never being able to use any of the currently available representatives of this class for later HIV-infection treatment may an acceptable one. |
The European Commission granted marketing approval for the nucleoside reverse transcriptase inhibitor abacavir (Ziagen) in all 15 member countries of the European Union, according to a statement from the drugs manufacturer Glaxo Wellcome. This follows a recommendation for full approval of abacavir by the European Union's Committee for Proprietary Medicinal Products in March 1999, and approval by the US Food and Drug Administration in December 1998.
Findings from clinical studies in previously untreated HIV-infected adults indicate that abacavir, when administered as part of combination antiretroviral therapy, significantly suppresses viral replication for up to 48 weeks, officials at the UK company said. Abacavir is administered twice daily with no dietary restrictions and has a low probability of drug interactions.
Source: CDC HIV/STD/TB Prevention News Update
Researchers followed a cohort of people with advanced HIV in Switzerland to in investigate the effect of antiretroviral therapy on AIDS-related Kaposi's sarcoma and non-Hodgkins lymphoma. Potent antiretroviral therapy was administered gradually starting in 1995. The researchers found that the incidence of new AIDS conditions dropped from 157 events to 35 events per 1,000 person-years in 1992 to 1994. Combination therapy was found to significantly reduce the rate of opportunistic infections. Kaposi's sarcoma was greatly reduced by potent antiretroviral therapy, but non-Hodgkins lymphoma did not decrease similarly.
Ref: BMJ 1999;319:24-25.
Source: CDC HIV/STD/TB Prevention News Update
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With HHV-8 being linked to both KS and NHL you would expect both diseases to decline with improved immune control of HHV-8. However, some believe that KS may represent ongoing HHV-8 infection, whereas NHL may only be triggered by HHV-8 and its disease process unaffected by this viruses control later on. It is encouraging that an increase in incidence of NHL was not observed. |
Two weeks treatment with recombinant growth hormone significantly increases lean body mass in HIV-infected individuals with acute opportunistic infection, according to a report in the July 9th issue of AIDS. Previous findings indicated that a 12-week course of growth hormone can improve the protein metabolism in patients with AIDS-related wasting, leading to increased lean body mass and improved functional status. However, growth hormone therapy is prohibitively expensive.
This led Dr. Nicholas I. Paton of St. George's Hospital in London and colleagues to investigate the effects of a 2-week course of growth hormone on HIV-infected men with acute opportunistic infections, which are commonly associated with weight loss. The subjects were treated with standard antimicrobial treatment and received intensive nutritional counselling and oral energy supplementation. Dr. Paton's group randomised the patients to receive placebo (11 men) or once-daily 6-mg subcutaneous growth hormone (9 men) for 2 weeks.
In the patients treated with growth hormone, they found that the "...protein catabolic rate decreased by 60% in the fasted state, lean body mass increased by 2.2 kg and fat mass decreased by 0.7 kg." Significant increases in grip strength were also seen at follow-up. In addition, no increases in adverse effects were noted in these patients. Conversely, Dr. Paton's group observed no significant changes in the placebo group.
Based on these findings, they suggest that for patients with HIV-related opportunistic infections a 2-week course of growth hormone "...may represent a rational and economical approach to the use of growth hormone therapy."
Ref: AIDS 1999;13:1195-1202.
Source: CDC HIV/STD/TB Prevention News Update
Abstract:
The effect of P-glycoprotein inhibition on the uptake of the HIV type 1 protease inhibitor saquinavir into brain capillary endothelial cells was studied using porcine primary brain capillary endothelial cell monolayers as an in vitro test system. As confirmed by polymerase chain reaction and Western blot analysis, this system functionally expressed class I P-glycoprotein (pgp1A). P-Glycoprotein isoforms pgp1B or pgp1D could not be detected. The uptake of saquinavir into endothelial cells could be described as the result of a diffusional term of uptake and an oppositely directed saturable extrusion process. Net uptake of saquinavir into cultured brain endothelial cells could be increased significantly up to 2-fold by SDZ PSC 833 in a dose-dependent manner, with an ic50 of 1.13 µM. In addition, the HIV protease inhibitor ritonavir inhibited p-glycoprotein-mediated extrusion of saquinavir with an ic50 of 0.2 microM, indicating a high affinity of ritonavir for p-glycoprotein. In conclusion, we showed that the HIV protease inhibitor ritonavir is a more potent inhibitor of P-glycoprotein than the multidrug resistance (MDR)-reversing agent SDZ PSC 833. The inclusion of this drug in combination regimens may greatly facilitate brain uptake of HIV protease inhibitors, which is especially important in patients suffering from AIDS dementia complex.
Ref: Drewe J, Gutmann H,. Fricker G et al. HIV Protease Inhibitor Ritonavir: A More Potent Inhibitor of P-Glycoprotein than the Cyclosporine Analog SDZ PSC 833. Biochemical Pharmacology 1999 May 15;57:1147-1152.
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Variable expression of P-gp in patient populations may in part explain the suboptimal response to PI's which are actively effluxed by the P-gp pump. Could the inclusion of RTV have additional benefits to CYP P450 modulation in double PI regimens by also inhibiting P-gp pump efflux? Additionally P-gp is inducable and the presence of any substrate (ie. PI's) may upregulate P-gp expression increasing efflux of PI from cells - a potential cause of longer term PI failure. In vivo studies of P-gp expression over time in recipients of different PI regimens will be needed to determine the real effects of these drugs on this mechanism. |
HIV-positive individuals who are long-term nonprogressors (LTNPs) have no distinctive virologic parameters, except for lower viral load and isolation rate, that distinguish them from those who do progress, according to French researchers.
Dr. Daniel Candotti of Hopital Pitie-Salpetriere in Paris and associates evaluated 68 LTNPs and 9 slow progressors who served as controls. The criteria for LTNP was at least 8 years of asymptomatic HIV infection, a stable CD4 cell count greater than or equal to 600/µL and no antiretroviral therapy. Although the investigators detected a wide range of plasma HIV RNA levels in all subjects, the median values were much lower in LTNPs compared with controls, at 6000 and 40,000 HIV RNA copies/mL, respectively. The LTNPs also had lower rates of viral isolation and cell-associated viraemia.
"By contrast, no major differences in virus replication properties or cell tropism were observed," they report in the July issue of the Journal of Medical Virology. "All LTNP isolates replicated in [monocyte-derived macrophages], and all but two were [nonsyncytium-inducing]." They observed a similar NSI phenotype for most of the control isolates. "The relative contributions of virological factors in determining the lack of progression of HIV disease still remain unclear in these subjects," Dr. Candotti's group concludes.
Despite the fact that 6 LTNPs progressed over the 1-year study period, they still believe there may be a subgroup of patients who will not progress "...since the follow-up indicated a great stability of virological parameters over this period for the majority of the LTNP subjects."
Ref: J Med Virol 1999;58:256-263.
Source: Reuters Health.
Roche Holding recently established a joint development agreement with Trimeris to conduct human clinical trials and complete development of two new AIDS drugs, T-20 and T-1249. The companies will split research costs and earnings from the drugs in the United States and Canada, but Roche will hold global marketing rights and handle development costs in other countries. Previous studies of T-20, which is in Phase II human trials, showed it reduced the amount of HIV in a patient's blood by as much as 99 percent in two weeks; T-1249 is only in the first stages of human testing.
Source: CDC HIV/STD/TB Prevention News Update
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T-20 is a fusion inhibitor, a new drug class of antiretrovirals. Resistance develops rapidly in vitro and rebound indicating resistance also occurred within 2 weeks when T-20 was used as monotherapy in multi-class failure patients. We are hoping that Roche's involvement will bring faster development, some compassionate access and availability of this compound for trials in Europe. |
ATP has been asked by HIV clinicians in Devon and Cornwall to remind all those travelling to the area to view the solar eclipse to remember to take adequate supplies of all their antiretroviral drugs with them. The funding and resources of the local National Health Services will not allow for dispensing of emergency supplies.
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ON THE NET
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"Immune Reconstitution and Immunotherapy in HIV Infection," an excellent one-hour overview of current knowledge about possibilities of immune-based therapy for HIV disease, went online last week on the Medscape site, http://hiv.medscape.com; the author is Bruce D. Walker, M.D., of Massachusetts General Hospital and Harvard Medical School. Anyone can use this review without charge, and for medical professionals, one hour of continuing medical education credit is available. For those who want more in-depth information, over 130 references are included.
Source: AIDS Treatment News, Issue 322.
Further summaries and reports from the Lipodystrophy and/or the Resistance Workshops are available on the web at:
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NEW ATP PUBLICATIONS
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'If there's one thing more stressful than deciding to go on treatment, it's having to change one you have just got used to.'"
ATP have revised their guide to salvage therapy. First produced in June 1998 and updated every four months, it is still the only 'consumer guide' which looks at this difficult area of when and how to make the best choices in changing treatment.
The booklet, written in an easy-to-understand format, stresses the importance of making every treatment count. Salvage treatment at it's most basic is just a strategy to make sure, as safely as possible, that you are able to benefit from new drugs which are currently being developed.
There is information on the importance of the most recent tests - viral load, resistance and drug level monitoring - and how to get them. And new sections on drug-free breaks, experimental treatments and combinations with more than five drugs.
This guide is available free.
For single or bulk copies please call:
Charles Bowman at ATP on 0171 407 0777
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ERRATA
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Issue 71 of ATP's "Doctor Fax" contained a report on a fatality thought to be due to an intreraction between sildenafil (Viagra) and ritonavir (Norvir). This fatality was reported in a letter to The Lancet (Lancet 1999, 35, 2071-2072).
In our comments we incorrectly stated that the man who died had been in the first few weeks of ritonavir therapy. This was incorrect in that he had been taking ritonavir with saquinavir for more than a year.
A previous fatality thought to be due to the interaction of ritonavir with MDMA (ecstacy) had occurred during the induction of ritonavir therapy.
AIDS Treatment Project
St Stephens House 115-129 Southwark Bridge Road London SE1 0AX
Tel: 0171 407 0777 Fax: 0171 403 4262 Email: admin@atp.org.uk Web site: www.atp.org.uk
TREATMENT INFORMATION PHONELINE 0645 47 00 47 (Mon & Wed 6-9pm)