Medical Consultant
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Antiretroviral Drugs and Treatment Strategies
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Two letters published in the October 10th issue of The Lancet criticise the recently updated British HIV Association (BHIVA) Guidelines for the management of HIV- infection. Philip Hay and Zuber Mitchla of St Georges Hospital, London and Julio Montaner and colleagues of the University of British Columbia both question the role accorded to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals.
Both letters express the opinion, supported by virology substudies of antiretroviral clinical trials, that the new guidelines downplayed the relative potency of triple combination regimens based on an NNRTI drug plus 2 nucleoside analogues when compared with protease inhibitor based triple combinations. The updated BHIVA guidelines had cautioned that NNRTI based regimens should not be used in those patients with baseline plasma HIV-1 viral loads of greater than 50,000 copies/mL.
However, the letters authors state that other analysis of nevirapine containing triple combinations do not support the view that viral suppression below the level of detection (400 copies/mL) is less likely in treatment na•ve patients with baseline viral loads above 50,000 copies/mL. Hay and Mitchla citing meta-analysis of nevirapine containing combinations and using a multivariate proportional hazards analysis suggest that an upper cut-off of 250,000 copies/mL is a more appropriate level when considering the potency of virologic suppression of nevirapine containing combinations. Montaner and colleagues emphasised that an analysis of their trial of nevirapine/ZDV/ddI did show an effect of baseline plasma viral load on the probability of sustained suppression with this regimen, but that there was no clear upper limit with regard to baseline viral load beyond which nevirapine was no longer effective at reducing or maintaining viral load at a low level. Both letters also emphasise that protease inhibitor containing regimens also exhibit the same tendency for reduced effectiveness of viral suppression at higher baseline viral loads which do not differentiate them from NNRTI containing combinations.
The letters also criticise the guidelines for suggesting that efavirenz, an NNRTI currently in development, may be superior to those NNRTI's currently available in it's antiretroviral potency and caution that it is yet to be clearly established that there is indeed any difference in virologic response with any triple combination regimen, whether NNRTI or PI based.
Author: Paul Blanchard, ATP. Ref: The Lancet, vol 352, October 10, 1998. p1226-27.
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The question remains - if all triple combinations (both PI and NNRTI based) display equal potency of viral suppression, and all show reduced efficacy in higher baseline viral loads what combination or strategy should be used in those patients at higher likelihood of incomplete suppression - dual PI based or PI+NNRTI based? In asymptomatics with higher viral loads there is reluctance to dual PI use due to concerns over metabolic disturbances and their long term consequences. Although all induction- maintenance studies have so far failed to demonstrate continued durability of suppression in the maintenance phase it is imperative that these strategies are investigated further with more creativity. Induction with 4 or 5 agents from all classes and maintenance with a standard triple combo, and switching studies - induce on dual PI and switch to NNRTI for maintenance, the role of hydroxyurea, all need further investigation. In those with high baseline viral loads would it be better to wait and see how much suppression is achieved with a triple combination and then intensify or go for maximum suppression upfront? Finally, what constitutes a "high" baseline VL requiring more than a triple combo? Guidance (and more data!) is obviously needed here. If NNRTI and PI based triple regimens are evenly matched in terms of virologic suppression, might there be other factors influencing choice between them? We have yet to see studies giving evidence of lymph node clearance, naive lymphocyte repopulation or reappearance of immune correlates of OI resistance with NNRTIÕs.
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Nevirapine is an NNRTI used in both first- line and salvage therapy. One of it's side effects however can be a rash in up to 20% of people which can be severe enough in around 5% of people to cause them to have discontinue use. The seriousness of this hypersensitivity reaction makes it dangerous to try and use nevirapine again in the future. After noticing that patients who were using prednisone, a corticosteroid, did not have this problem, a study by Kaspar of Austin, Texas study looked into whether this was just a coincidence. Out of 155 patients, 83 people were offered 40-50mg daily of prednisone for the 14 day nevirapine induction period. In this group only one person developed a significant rash which was mild enough to continue treatment. Of the 72 patients not receiving prednisone, 10 developed a rash severe enough to warrant discontinuation of nevirapine.
Author: Simon Collins, ATP. Reference: ICAAC Abstract I-64a
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An alternative strategy may be to reinitiate nevirapine under corticosteroid cover in those patients with rash on first use. Some physicians have reported success with a 14 day cover using this strategy, thus avoiding unnecessary steroid treatment of the other 85-90% unaffected by rash. Prospective trials are now needed, perhaps comparing both strategies.
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This August Abbott Labs announced that unexplainable crystallisation within the capsules formulation of ritonavir, would require all patients to transfer to the liquid formulation (see DrFax 52). This problem of crystallisation effected the capsules but not the Norvir liquid if the liquid is stored properly (68-77 degrees fahrenheit).
On October 15th the company held a meeting for about 50 community representatives from the US, Canada, Western Europe, and South America to provide further information about these manufacturing supply problems.
Although it was stressed that any capsules which have been released to the public prior to this problem were properly screened and are safe and fully effective, the company was still unable to give an indication of when an alternative to the liquid formulation would be available. Despite cleaning and reconditioning manufacturing lines, installing new facilities and investing several million dollars to build new manufacturing facilities, the company have been unsuccessful in their attempts solve this problem. They still do not know why the problem occurred but it appears that there may be no going back from what has been called the Òtype 2Ó less soluble form of ritonavir.
Abbott are no longer trying to produce the original capsule formulation, and are focusing their resources on replacing the old capsule with a new 'Soft Elastic Capsule' (SEC). The SEC is being designed to be able to work with the crystallised formulation but the timetable for production and approval means the SEC will not be available in 1998 and it may be well into 1999 before the SEC may be
commercially available in the US. Author: Simon Collins, ATP.
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Liquid formulation raises adherence problems with many patients who have difficulty tolerating the taste. Although there are many suggestions to make this more palatable, the practicalities of carrying and taking a liquid, which has to be measured very exactly, creates many difficulties. |
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Given the key role of ritonavir when used with either saquinavir or indinavir within double- protease combinations, clinicians should be especially aware of adherence problems which may arise both with existing patients and patients who will start combinations using the liquid formulation. It may be helpful for some patients to hold back a supply of their capsules (kept refrigerated) for when carrying and storage of the liquid formulation is impossible (for example holidays away). Leaflets with adherence suggestions are also likely to be useful. (Available from ATP office 0171 407 0777). |
A team of Spanish researchers investigated virus-specific CD4 T-cell helper responses in patients receiving highly active antiretroviral therapy (HAART). The responses are not usually detected in people with early HIV infection. CD4 T-cell proliferation and response is associated with viraemia control in a few long- term non-progressors and in patients whose viraemia is controlled by HAART before seroconversion. The researchers divided 159 asymptomatic HIV-1 infected people into different groups receiving triple therapy, double therapy, or no therapy. They measured Proliferative response to pokeweed mitogen, recall antigens, tetanus toxoid, a ubiquitous antigen cytomegalovirus, and three HIV-1 recombinant proteins. They found that there was a lack of specific T-cell response to the HIV-1 proteins in all of the individuals and that other responses were similar as well. "Treated patients also lacked significant T-cell responsiveness to gp160...p24...or gp120," Dr. Gatell and colleagues report. "This non- responsiveness to HIV-1 antigens occurred in both groups of double and triple therapy." The authors note that the data indicates, "HAART alone will most likely not be enough to restore HIV-1-specific T-cell helper responses in people with chronic HIV-1 infection," and they suggest that other therapeutic strategies be investigated.
Source: CDC HIV/STD/TB Prevention News Update. Ref: Lancet 1998;352:1194-1195.
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These conclusions are based on only 8 patients who were <20 copies for up to 8 months. (up to? So how long exactly? - the research letter does not state). Other studies (such as Autran) suggest that more than 12 months is needed before any reappearance of these responses can be expected. Those unwilling to simply wait are investigating the role of cytokines such as IL-2 and HIV vaccination strategies under antiretroviral cover. |
Abstract Objective: To evaluate the efficacy of combination protease and reverse transcriptase inhibitor therapy in correcting HIV-1-induced lymphocyte subset abnormalities in previously treated adults.
Design: A 48-week observation study of lymphocyte subsets in 12 participants in the Multicenter AIDS Cohort Study who were already taking at least one reverse transcriptase inhibitor and added a protease inhibitor to their treatment regimen. Comparison groups were HIV-seronegative homosexual men, HIV- seronegative heterosexual men, and homosexual HIV-1-infected men who were long-term non-progressors.
Methods: Three-colour immunofluorescence and monoclonal antibodies were used to assess HIV-1-induced lymphocyte subset alterations related to immune deficiency and immune activation. Plasma HIV-1 RNA levels were monitored to assess suppression of viral replication.
Results: CD4+ cell counts significantly increased and lymphocyte activation measured as CD38 and HLA-DR expression on CD8+ T cells significantly decreased by 48 weeks. CD4+ cell values remained abnormal even in those who were fully suppressed. Some T-cell activation markers decreased to levels observed in long-term non-progressors. The increase in CD4+ T-cell numbers reached a plateau by week 24, but the increase in resting HLA-DR- CD38- T cells was sustained through week 48. Proportions of CD45RA+ CD62L-selectin+ and CD28+ CD4+ T-cell subsets and Fas expression were not abnormal at baseline compared with seronegative homosexual controls.
Conclusions: the most significant impact of suppression of viral replication was reversal of T-cell activation. However, normalisation of lymphocyte subset perturbations associated with chronic HIV-1 infection was not achieved after 1 years of treatment with current combination antiretroviral regimens. More profound viral suppression, therapy for longer than 1 years, or immunologic augmentation may be needed to fully reverse the abnormalities.
Ref: Giorgi JV, Majchrowicz MA, Johnson TD, Hultin P, Matud J, Detels R. AIDS 1998 Oct 1;12:1833-1844.
In the October issue of the journal AIDS, a team of scientists report taking an important first step toward speeding up the process. In a study of the anti-viral drug ritonavir involving 41 HIV- positive children, the scientists found that by performing a combination of tests earlier than is now standard, they could reliably predict within a week of starting the therapy whether or not the drug would be effective. Their prediction was correct in nearly nine out of 10 children.
"The essence of our analysis is that only a combination of multiple parameters reflecting the function of the immune system, level of viral replication, and drug pharmacology contains sufficient information to robustly predict long-term treatment efficacy from short- term measurements," said Dimiter Dimitrov, Ph.D., Sc.D., a scientist with the National Cancer Institute (NCI) and senior author of the study.
According to the study's lead author Brigitta Mueller, M.D., formerly an NCI scientist and currently at Harvard Medical School, the analysis should be applicable for combinations of drugs, even though the study evaluated initial therapy with a single drug. In fact, when 39 children from the study later began a triple- drug combination of ritonavir, zidovudine, and didanosine, Mueller and colleagues used the model to predict correctly the treatment outcome of 80 percent of the children.
Mueller added that the analysis also could potentially have implications for HIV-positive adults. "There obviously are major differences between children and adults," said Mueller of the study, which involved a collaboration of scientists from NCI and Abbott Laboratories in Abbott Park, Ill. "But our results showed some similarities between children and adults in the rate of virus clearance, one of the key parameters of the analysis."
Currently, doctors evaluate a person's long- term prognosis based on two tests: counts of CD4 immune cells and the amount of HIV present in the blood. Previous studies have suggested that changes in the concentration of the virus several months after the start of therapy can be predictive of a person's long- term risk of developing AIDS. However, if the therapy is suboptimal, the children are unnecessarily exposed to drug toxicity and the virus can develop resistance to the drug.
The analysis that Mueller et al., developed takes goes one step further. By using four parameters Ñ the pretreatment levels of CD4 cells and HIV RNA in the blood, the plasma drug concentration at the end of the first week on therapy, and the rate of virus elimination from the blood Ñ the scientists could predict the HIV blood concentration three months after the initiation of therapy, a measure that is related to the likely risk of developing AIDS and dying.
In the current paper, the team used data collected during a Phase I clinical trial, the first step in evaluating a treatment in people. A Phase I study serves to make sure that a drug is safe, then its dosage is gradually increased to determine the best and most effective dose.
The scientists found that after 12 weeks of treatment, it was possible to divide the children, based on changes in their plasma HIV concentrations, into two broad categories of good or poor responders to the drug. They also discovered that about half of the children who fell into the "poor responder" group remained there even after receiving the highest possible dose of the drug, while several children in the "good responder" category benefited from relatively small amounts of ritonavir. This indicated to them that factors other than how much drug a patient receives had to be at work in determining the effectiveness of the treatment.
To tease out these factors, the scientists went back and analysed tests that they had performed for each child during the first week of the study. The scientists discovered a number of similarities in the good responders. They had consistently higher rates of viral clearance, coupled with higher plasma concentrations of ritonavir, an indication that the drug stayed in their systems longer than the poor responders. The good responders also had a lower viral load count Ñ an indication of low levels of virus replication Ñ and higher CD4 cell counts Ñ a sign of better immune function.
"These findings suggested that it might be possible to use these data from the first week of treatment to predict a child's chances of being a long-term responder to the drug," said Steven Zeichner, M.D., Ph.D., an NCI scientist and an author on the paper.
The scientists plugged these parameters into a mathematical prediction method for each child in the study. Based on this analysis, they found that they had accurately predicted the long-term response of 36 out of 41 children. They also noted that for three other children in the study, they were unable to make a prediction one way or the other based on the analysis.
"These results are extremely encouraging," said Dimitrov. "But they represent a first step, and they do need to be tested further in more patients and other settings." Source: NATIONAL INSTITUTES OF HEALTH. National Cancer Institute.
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In the absence of rapid access to more potent, less toxic, user friendly agents urgent attention is needed now to those technologies available today which will increase the margin of success of antiretroviral therapy - resistance testing and therapeutic drug level monitoring. Variable pharmacokinetics with NNRTIÕs and PIÕs reflect variability in cytochrome p450 activity across populations. Trough levels consistently appear the most important parameter in sustained suppression. ÔSteady stateÕ levels establish relatively quickly with most agents and checking these at 1-2 weeks to see if trough values are high enough would seem prudent. Compared to drug costs of HIV treatment, the cost of such testing is minimal and offers savings on treatment failure, escalating agents in multiple regimens and treatment of drug induced toxicityÕs. Patients must demand access to available technologies now to aid compliance and reduce the use of drugs which are not adding anything to the potency of a given combination. |
Gilead Science has been developing a class of broad-spectrum antiviral agents called nucleotide analogues for over five years. To date, cidofovir (Vistide) has been approved for the treatment of AIDS-related CMV retinitis and adefovir (Preveon) is in an expanded access program for the treatment of HIV. Both compounds have proven antiviral activity and long half-lives in the body, which allow for less- frequent dosing. Unfortunately, both compounds are also associated with the development of potentially serious side effects, including damage to the kidneys.
Intravenous hydration with at least one litre of saline solution should be administered prior to each infusion of cidofovir. Three doses of oral probenecid must be administered the day of the infusion. (Probenecid is a drug that prevents the kidneys from absorbing the cidofovir.) Renal function must be monitored 48 hours prior to every dose. In the event that serum creatinine and urine protein levels are elevated, cidofovir dosing should be reduced or discontinued. If all of these guideline are rigorously followed each time the drug is administered, the risk of renal toxicity is reduced.
In addition to the high incidence of kidney problems, a higher rate of uveitis (inflammation of the eye) has been reported than had been anticipated based upon clinical trial experience. The rate of eye inflammation was under 5% in trial participants, but since the drug was approved, ophthalmologists from three university clinics have reported rates of 50% in patients receiving cidofovir therapy for 125 days (JL Davis et al. Archives of Ophthalmology. June 1997; 115(6):733-7). Patients with more advanced CMV disease are more prone to uveitis.
Any eye inflammation after an infusion should be reported to the ophthalmologist immediately, as continued dosing with full- strength cidofovir can exacerbate the situation. Uveitis can lead to scarring and loss of sight. Although it can be treated with topical steroids, there is a risk for the development of cataracts. Hypotony, a serious condition of reduced pressure in the eyeball, can also occur, so intraocular pressure should be monitored.
Finally, three cases of hearing loss associated with cidofovir have been reported. Upon discontinuation of therapy, the hearing impairment abated. Janet Davis, M.D., of the University of Miami, summed things up by stating, "I think cidofovir is an excellent drug -- it works for the retinitis -- but it is very, very toxic. It has to be treated with extreme respect."
There is only preliminary data to support the efficacy of the 60 mg dose and none to support the 30 mg dose. The data available on 60 mg comes from Protocol 417, which compares doses of 60 mg and 120 mg in combination with other antiretroviral agents, including protease inhibitors. Since the study is still ongoing, investigators do not know which dose participants are taking. After 20 weeks of therapy, efficacy results are comparable between the two groups, but the potent antiviral effect of the protease inhibitors might obscure any impact from either dose of adefovir. One dose level does appear to be better tolerated with respect to renal toxicityÕs. Gilead is betting that this is the 60 mg dose.
Monthly lab tests are required to monitor creatinine, electrolytes, liver function, urine protein and glucose. It remains to be seen whether Gilead can find a dose of adefovir that is both potent and well tolerated. Until then, patients will have to decide whether the benefits of adefovir, especially at lower doses, are worth the potential toxicityÕs.
Participants were broken down by baseline genotypic resistance mutations. Between 70% and 90% had previously used 3TC and over 90% had previously used AZT for an average of three years. In this heavily pretreated group, 76% at baseline had the codon 184 mutation associated with 3TC resistance. All participants in the substudy continued using 3TC in their regimens. The participants with the 184 mutation alone achieved a 0.94 log (88%) decrease in viral load at week 24. Participants with the 184 mutation plus high-level AZT resistance (as defined by mutations at codons 41 and 215) experienced a 0.51 log (69%) reduction in viral load. Confirming that adefovir is ineffective against AZT-resistant HIV, the worse antiretroviral response, an average 0.05 log (11%) reduction, was seen in participants with high-level AZT resistance without the 184 mutation. (The few study participants with none of these mutations experienced a 0.65 log (78%) viral load reduction.)
The addition of the 184 mutation seems to increase HIV's sensitivity to adefovir, although the durability of this effect is unknown because of HIV's propensity to develop further compensating mutations. Still, Gilead may position adefovir as salvage therapy for the large AZT/3TC experienced population with few other treatment options. Although the viral load reductions are not huge in this group, they are better than the 0.39 log (59%) reductions seen by the 408 cohort as a whole. Choosing a drug based on the presence of specific resistance mutations is a novel concept, but as more is learned about the significance of genotyping, this may become a useful means for tailoring treatment regimens. Author: Jill Cadman Source: GMHC Treatment Issues, Vol. 12, No. 9 - September 20, 1998.
US researchers have shown that the gene encoding HIV integrase shows very little variance between or within HIV-infected subjects. This low level of mutagenesis, they say "...should encourage the pursuit of anti- integrase therapies."
The researchers, led by Dr. Michael Katzman, of The Pennsylvania State University College of Medicine in Hershey, compared the genetic sequences coding for integrase from five HIV-infected patients who showed no signs or symptoms of illness for more than 7 years with those from five who progressed rapidly to AIDS.
The researchers detected "...no amino acid changes that might account for the variable rate of disease progression between patients." No differences were seen between sequences from the same patient taken at early and late time points in infection.
These results suggest that the integrase gene "...may be the most constrained" of the coding regions in the HIV-1 pol gene, which also includes the protease and reverse transcriptase coding regions, Dr. Katzman and colleagues write in the October 1st issue of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology.
"This bodes well for the design of antiretroviral agents that target [integrase]," they suggest, "because biologic constraints [on the integrase gene sequence] may prevent the development of drug resistance."
Source: CDC HIV/STD/TB Prevention News Update Ref: J Acquir Immune Defic Syndr Hum Retrovirol 1998;19:99-110.
Currently licensed anti-HIV therapy attacks two vital HIV enzymes, reverse transcriptase (RT) and protease. Eventually, however, these therapies begin to fail in some people, even when both enzymes are targeted. Integrase is a third enzyme that HIV needs in order to turn cells into virus factories. Although a number of pharmaceutical companies have been developing integrase inhibitors for several years, none of them have proven effective.
Researchers at the University of California at Irvine have been studying plant extracts containing compounds which attack integrase. Plants which were found to have this activity include extracts of chicory, green coffee beans and artichokes. These plants yielded chicoric acid, which in laboratory experiments with cells had potent anti-integrase activity and very low toxicity.
Unfortunately, chicoric acid cannot be used on its own for long because, as with most compounds, HIV eventually becomes resistant to its effect. Hope remains, however, that chemists will now be able to design other, perhaps more potent, integrase inhibitors to create a whole new class of potential anti-HIV drugs.
Ref: Journal of Virology 1998;72(10):8420-8424. Source: "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca"
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"Following 3 months of selection...HIV-1 was completely resistant to the compound," they report. The investigators then sequenced the integrase gene from the resistant strain and identified several mutations including one at position 4025 coding for a glycine to serine transition at amino acid 140. To test whether this mutation was responsible for the resistance to L-chicoric acid, Drs. King and Robinson cloned the integrase genes from the resistant HIV strain into native HIV-1. They report that the strain with the mutant integrase "...was resistant to the anti-HIV effects of L-chicoric acid." The virus remained sensitive to zidovudine. "These results confirm...that L- chicoric acid inhibits integrase and that the drug is likely to interact at residues near the catalytic triad in the integrase active site," the researchers conclude.
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In a letter to the editor of the Lancet, Johan R. Boelaert of Algemeen Ziekenhuis St- Jan in Belgium and Kirk Spencer of Mount Sinai School of Medicine in New York City, call for less expensive antiretroviral therapies in the developing world. They suggest that the combination of hydroxyurea, didanosine, and chloroquine may be a worthwhile regimen. In addition to the anti-HIV effects of the medicines, chloroquine may also be useful against opportunistic infections such as Mycobacterium tuberculosis. They examined the effects of the drugs in vitro and found that the regimen reduced p24 antigen and reverse transcriptase activity. They suggest that the results warrant further testing. Source: CDC HIV/STD/TB Prevention News Update Ref: Boelaert, Johan R.; Sperber, Kirk. Lancet (10/10/98) Vol. 352, No. 9135, P. 1224;
Hoffmann-La Roche has said that it will donate saquinavir, ddC, and AZT to hospitals in Kenya, Tanzania, Uganda, Zimbabwe, Zambia, Malawi, Cameroon, and the Ivory Coast. The drugs are valued at 400,000 British pounds; when supplies run out, the company said it will sell the drugs at reduced prices. Hoffmann-La Roche will purchase the AZT from rival Glaxo Wellcome. Some advocates say the measure is not enough, claiming that ddC and saquinavir are inferior to other anti-HIV drugs on the market. Others praised Hoffmann- La Roche for the contribution, but warned that the supplies should be maintained and that patients should be observed for adherence. Agathe Lawson, the Joint UN Program on HIV/AIDS advisor for the Ivory Coast, said, "The donations are definitely a good thing because the situation in Africa is so urgent."
Source: CDC HIV/STD/TB Prevention News Update Ref: New Scientist (09/26/98) Vol. 159, No. 2153, P. 20; Day, Michael
Dr. Kathleen M. Melbourne of the University of Rhode Island in Providence and colleagues have concluded that when used alone, self-reports of drug adherence do not provide an accurate assessment of compliance among HIV-infected individuals. The researchers compared self-reported rates of adherence with an electronic monitoring system, finding that self-reported rates of adherence were consistently higher than rates observed with the monitoring system. Electronic monitoring indicated that up to 43 percent of subjects did not take their protease inhibitors within two hours of the self-reported time and only one of 44 patients took 100 percent of the doses in a three-month period. The researchers, who reported their findings at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy in San Diego last month, also found that 24 percent of the subjects overestimated the number of doses they took by more than 10 percent.
Source: CDC HIV/STD/TB Prevention News Update
The advent of triple-drug therapy for HIV disease has raised the concern that disadvantaged patients with multiple social problems may be nonadherent to treatment. Fearing that partial adherence will lead to drug resistance, some clinicians are withholding these powerful new drugs from such patients. The historical record demonstrates that labelling patients as nonadherent may be both stigmatising and inaccurate. Since 1900, such adjectives as ignorant, vicious, and recalcitrant have been used to describe patients who do not follow medical advice. Less judgmental terms, such as nonadherent and noncompliant, are now used, but these terms still imply that patients should obey physician-imposed regimens. Studies of nonadherence have consistently shown that the problem is widespread among all persons and cannot reliably be predicted on the basis of patient characteristics. This paper argues that physicians should de-emphasise the standard approach of predicting and correcting nonadherent behaviour in certain patients. Rather, clinicians should encourage all HIV- positive patients to devise individualised treatment plans that can facilitate reliable ingestion of medication. Although the potential development of resistance to triple-drug therapy remains an important public health issue, concern about this possibility must be balanced with respect for patients' rights. Encouraging the active participation of HIV-positive persons in their own treatment will help avoid judgmental and inaccurate assessments of patient behaviour and may help patients take medications more successfully.
Ref: Lerner BH, Gulick RM, Dubler NN. Ann Intern Med 1998 Oct 1;129(7):573-8
Protease inhibitor therapy has helped to increase the life span of many HIV-infected people, only to leave them attempting to adjust to what is--for many--life after death. A number of patients have seen their friends die from AIDS, and they face a harder life with the virus. Patients may face financial difficulties due to the cost of treatment or anxiety over the end of romantic relationships; some even become suicidal.
Researchers have dubbed this anxiety the Lazarus Syndrome, named after the biblical figure who was raised from the dead by Christ. Dr. Judith Rabkin, a professor of clinical psychology at Columbia University, estimates that tens of thousands of HIV-infected people may have the syndrome. While the rigid medical regimen of protease inhibitor treatment may not directly cause the syndrome, it can contribute to the anxiety. Researchers note that the syndrome is unique to AIDS but liken it to feelings of trauma suffered by Holocaust survivors. Both groups have seen their friends and families die and expected that they too would die, but were saved instead. Doctors are hesitant to prescribe anti-depressant medication for HIV-infected patients who develop depression, because the medications may interact poorly with the AIDS drugs. Some advocacy groups are offering counselling to help patients deal with their emotions.
Source: CDC HIV/STD/TB Prevention News Update Ref: New York Times (10/06/98) P. D7; France, David
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OBSTETRICS & PERINATAL TRANSMISSION
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Current federal guidelines were put in place after discovery in 1994 of a new therapy that reduces by two-thirds the chance that an infected woman will pass HIV to her child. The guidelines advise health care providers to give extensive pre-test counselling to all pregnant women, educating them about the risks of AIDS and the benefits of being tested. These guidelines led to an increase in testing and treatment. But because many women are not tested and do not receive treatment, the number of children born with HIV is still unacceptably high, the report says.
"We have the tools to prevent HIV infection in new-borns. Now we must get treatment to everyone who needs it," said committee chair Marie McCormick, professor and chair, department of maternal and child health, Harvard School of Public Health, Boston. "By making HIV screening a routine part of prenatal care for all pregnant women, regardless of their risk factors or where they live, we can further lower the number of paediatric AIDS cases and help infected women get high-quality treatment."
Making prenatal testing routine would help lower many of the barriers that keep women from being tested. It would reduce the burden on prenatal care givers to provide the extensive pre-test counselling required by current guidelines. Providers would no longer have to decide whether to encourage some women more than others to be tested, an approach that results in many cases being missed. It would lessen the stigmatisation of groups in which perinatal HIV transmission is now more prevalent, which include African American and Hispanic women. And it would guard against geographic shifts in the incidence of HIV infection, which is more common among women in large cities and in parts of the northeastern and southern United States. The costs of routine prenatal testing compare favourably with the costs of treating children who have HIV.
Source: CDC National Center for HIV, STD and TB Prevention
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The routine offer of HIV-testing to all pregnant women has been debated in the U.K but uptake lags behind other European countries. Debates on policy, opt-in or opt-out approaches, are yet to be settled between midwives, obstetricians and HIV physicians. While talk goes on some mothers giving birth are still unaware of their HIV status and its implications to themselves and their child.
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Pregnancy does appear to increase the risk of disease progression, AIDS-defining illness, and mortality for HIV-positive women, according to the first systematic review of studies of pregnancy in HIV infection. Drs. Rebecca French of the Mortimer Market Centre, London, and Peter Brocklehurst of Radcliffe Infirmary, Oxford, UK, reviewed seven prospective cohort studies published between 1983 and 1996. They performed statistical analyses on the combined results of these studies.
They report that the odds ratio for death was 1.8 for pregnant HIV-positive women compared with nonpregnant HIV-infected women. The odds ratios for disease progression and progression to an AIDS-defining illness were 1.41 and 1.63, respectively. The results appear in the August issue of the British Journal of Obstetrics and Gynaecology.
"The findings of this review have implications for women infected with HIV who are pregnant or are considering a pregnancy," Drs. French and Brocklehurst write.
"Pregnant women and those women thinking about becoming pregnant need to be counselled and advised about the possible risks to their own health as well as any transmission risks before they can make an informed decision on how to proceed."
The researchers also performed an analysis of perinatal outcome associated with maternal HIV infection in 31 studies published between 1983 and 1996. They found that for pregnant women with HIV-infection, the risk of spontaneous abortion relative to the risk for uninfected women was 4.05. The odds ratios for stillbirth, foetal abnormality, and infant mortality were 3.91, 1.08, and 3.69, respectively.
They note that "...the association between infant mortality and maternal HIV infection was stronger in studies conducted in developing countries when compared with developed countries."
In an accompanying comment, a journal editor notes that the results of these studies "...give additional reasons for screening pregnant women for the immunodeficiency virus." Source: CDC HIV/STD/TB Prevention News Update Ref: Br J Obstet Gynaecol 1998;105:827-848.
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The period of 1983-96 is a long period during which many changes in treatment of both HIV and OIÕs has occurred. It is not clear if the increased risk is still observable in the later studies. Was the analysis adjusted for HIV- treatment as a confounder?
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PATHOGENESIS
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Abstract Background. Human immunodeficiency virus (HIV) infection is increasingly recognised as an important cause of dilated cardiomyopathy. However, the pathogenesis of the heart-muscle disease in the acquired immunodeficiency syndrome is unclear.
Methods. We performed a prospective, long-term clinical and echocardiographic follow-up study of 952 asymptomatic HIV- positive patients to assess the incidence of dilated cardiomyopathy and to analyse the clinical variables associated with the development of cardiomyopathy. All patients with an echocardiographic diagnosis of dilated cardiomyopathy underwent endomyocardial biopsy for histologic, immunohistologic, and virologic assessment.
Results. During a mean (±SD) follow-up period of 60±5.3 months, an echocardiographic diagnosis of dilated cardiomyopathy was made in 76 patients (8 percent), with a mean annual incidence rate of 15.9 cases per 1000 patients. The incidence of dilated cardiomyopathy was higher in patients with a CD4 count of less than 400 cells per cubic millimetre (as compared with a CD4 count of greater than or equal to 400 cells per cubic millimetre) and in those who received therapy with zidovudine. A histologic diagnosis of myocarditis was made in 63 of the patients with dilated cardiomyopathy (83 percent). Inflammatory infiltrates were predominantly composed of CD3 and CD8 lymphocytes, with staining for major histocompatibility complex class I antigens in 71 percent of the patients. In the myocytes of 58 patients, HIV nucleic acid sequences were detected by in situ hybridisation, and active myocarditis was documented in 36 of the 58. Among these 36 patients, 6 were also infected with coxsackievirus group B (17 percent), 2 with cytomegalovirus (6 percent), and 1 with Epstein-Barr virus (3 percent).
Conclusions. Dilated cardiomyopathy may be related either to a direct action of HIV on the myocardial tissue or to an autoimmune process induced by HIV, possibly in association with other cardiotropic viruses.
Ref: Giuseppe Barbaro, Gabriella Di Lorenzo, Benvenuto Grisorio, Giorgio Barbarini, N Engl J Med 1998;339:1093-9.
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Considering the rising incidence of HIV- associated cardiomyopathy, Dr. Barbaro and colleagues recommend that "...a careful cardiologic evaluation should be made to detect early involvement of the heart in HIV- positive patients."
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HIV infection can result in the over- expression of glial cytokines in the central nervous system, a process which is also implicated in Alzheimer's disease pathogenesis. Risk of Alzheimer's is associated with the E4 allele for apolipoprotein E (APOE). Researchers from Sweden, Denmark, and the United States attempted to determine whether the presence of the E4 isoform in HIV-infected people is correlated with higher rates of dementia. They examined 11 HIV-positive people with the allele and 33 infected people without it. The scientists found that twice as many subjects with the E4 allele were demented or had peripheral neuropathy at least once. The authors conclude that "the response of the nervous system to HIV infection may be at least in part genetically determined by the presence or absence of the gene encoding the APOE E4 isoform." They note that long-term HIV survivors with the E4 isoform may be at higher risk for the development of Alzheimer's and that gene-viral interaction may accelerate Alzheimer's pathogenesis.
Ref: Corder, Elizabeth H.; Robertson, Kevin; Lannfelt, Lars; et al. Nature Medicine (10/98) Vol. 4, No. 10, P. 1182;