Medical Consultant
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TREATMENT STRATEGIES
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Paul Blanchard, ATP.
Cell mediated immune responses against HIV are believed to be the major controlling factor in those infected persons able to contain viral replication without antiretroviral therapy, so called long term non-progressors. These responses are characterised by strong T-helper lymphocyte proliferation responses against core (p24) HIV antigens.
Successful antiretroviral therapy reduces viral replication to very low levels and allows partial reconstitution of immune responses even in those with advanced immunodeficiency. There has, however, been little evidence so far that recovery of host immune responses to HIV itself takes place, even with prolonged antiretroviral treatment. In fact, in those patients who display evidence of these responses prior to antiretroviral treatment, the responses have been seen to weaken and may disappear all together if viral suppression is successful.
This disappearance of host responses to HIV is perhaps unsurprising given that maintenance of cell mediated responses normally requires ongoing stimulation through the continuing presence of viral antigen. As viral turnover is reduced to very low levels by antiretroviral therapy infected cells no longer produce viral antigens and stimulation of host responses wane. Indeed, the reduced activation state of lymphocytes is taken as a marker of successful therapy with anti-HIV drugs.
The paradox in this situation is that prolonged and unremitting antigenic stimulation accompanying uncontrolled HIV replication does not sustain anti-HIV host responses but is thought to be responsible for their demise. This may be happening through hyperactivation and exhaustion of the immune system, or by the destruction of the T-helper cells promoting these responses. The activated T-helper lymphocytes are one of the primary targets for HIV-infection itself.
It has been suggested that sufficient stimulation of anti-HIV cell mediated responses by immunisation with modified forms of HIV while the native infection is being suppressed by antiretrovirals may reverse the anergy of host responses accompanying chronic infection. One of the leading candidates to test this approach is the immunising antigen known as Remune(, developed by Jonas Salk and the Immune Response Corporation and being carried forward into clinical trials by Agouron Pharmaceuticals.
This product is a whole killed vaccine prepared from HIV-1 with a clade A envelope and clade G gag. The outer envelope protein (gp-120) is depleted and the subsequent antigen preparation inactivated both chemically and by irradiation.
In a paper to The Journal of infectious diseases, Ronald B Moss and Mark Wallace report the results of a study that assessed immune recognition of HIV after stimulation with the Remune vaccine combined with potent antiviral drug therapy. HIV-1 specific lymphocyte proliferation in 15 HIV-infected subjects was measured before and after immunisation while combination antiretroviral therapy was maintained.
The subjects had mean baseline CD4 count of 586 cells/mm3 (range 223 - 1147) and plasma HIV RNA of 953 copies/mL (range <400 - 4625). A variety of antiretroviral combinations were used but all consisted of 2 nucleoside analogues together with one or two protease inhibitors. The HIV-1 immunogen (Remune) was administered at day 1 and every 12 weeks thereafter and consisted of the gp-120 depleted inactivated HIV-1 at a dose of 10 U of p24 antigen in incomplete Freund's adjuvant.
The subsequent in vitro immune function assays used a range of antigens: the complete gp-120 depleted immunogen, p24 antigen purified from the Remune vaccine (np24), a recombinant p24 (rp24) and Candida antigen as a control. Recognition of these antigens was assessed before and after treatment (immunisation) by standard lymphocyte proliferation assays (LPA) and by a flow cytometry method. Additional proliferation assays were also performed on PBMC's depleted of CD4, CD8 and NK cells (CD56). Chemokine production responses to antigen were measured by ELISA of MIP-1(.
After the first injection of immunogen a significant augmentation of responses to the immunising antigen, purified np24 and rp24 was observed. In contrast, responses to Candida antigen did not significantly change after treatment. These responses were not further stimulated with additional injections but remained significantly elevated from pre-treatment levels throughout the study period. Antigen specific flow cytometric assays revealed that CD4, CD8 and NK cell phenotypes were the predominant cells proliferating in response to HIV antigen. Increased production of HIV antigen stimulated (-chemokine (MIP-1() after treatment with HIV immunogen was also observed. Cell depletion studies revealed that depletion of Th (CD4) cells resulted in the strongest abrogation of the HIV specific lymphocyte proliferation response.
The study authors conclude that "...the results of the study suggest that HIV-1 functional immune unresponsiveness can be reversed by an HIV-1 specific immune-based therapy in chronic HIV-infection."
Ref: Moss RB, Wallace MR, Giermakowska WK, et al. Journal of Infectious Diseases, 1999; 180:641-8.
Full paper is available on the Web at:
http://www.journals.uchicago.edu/JID/journal/contents/v180n3.html
Summary and translation: Emmanuel Trenado, TRT5 and Simon Collins, ATP
The French Department of Health has just issued revised guidelines for the treatment of HIV. The drafting committee of around 30 people is made up of an expert panel from both leading medical specialists and representatives from HIV community treatment organisations.
First drafted in May 1999, the guidelines are now published (in French) as a 230 page paperback - and this revised version is written in a clear and easy to understand language and includes chapters on treatment of children, pregnancy, HIV-2, immunotherapy, adherence and hepatitis. It is also accessible on the Internet:
http://www.sante.gouv.fr/htm/dossiers/sidahop/index_delfra.htm
It is particularly significant that the guidelines are not based purely on evidence based medicine and that they comment on recent controversial reports and findings. Each chapter allows for an in-depth discussion of the issues involved. The following summary concentrates on differences to current UK guidelines, and highlights the summary recommendations from the report, which are given at the end of each chapter.
Virological monitoring
Similar to current UK guidelines, the primary goal of antiretroviral treatment is recognised as maximal and sustained viral suppression (preferably <20copies) and that new viral load tests sensitive to <50 copies enable effective monitoring at these levels. It is also recommended that patients are always monitored using the same make of test.
Resistance tests
It is recognised that resistance to antiretroviral treatment is one of the causes of therapeutic failure and that tests now are available that can help measure this.
Recommendations:
ii) Recommended PIs in first line combinations are indinavir, nelfinavir and ritonavir. Saquinavir (Fortovase) is not recommended as a single PI when used in a first-line combination due to the high daily pill count required.
iii) Dual-PI regimens are surprisingly not recommended as a first-line option
iv) ddC is not included in the recommended NRTIs for first-line treatment because of difficult side effects.
v) Triple nucleoside combinations, particularly AZT/3TC/abacavir are not recommended as first line therapy. The guidelines listed the following possible points in favour of using triple nucleosides:
It is interesting that a specific section has been included on managing combinations which are virologically successful but which are difficult to tolerate for individual patients. Because anti-HIV treatment strategies are long-term, the impact of a treatment on quality of life should be taken into account and this may require modification of the original treatment. Any antiretroviral treatment cannot be definitely settled on even if it is the current standard of care and it is working.
Recommendations:
* Any switch should continue to aim to achieve maximal viral suppression
For example, in the case of intolerance to NRTIs
Virological failure:
The importance is stressed for understanding the reasons behind each individual case of treatment failure such as previous treatment history, checking for PK interactions with other medications and difficulties of adherence.
Patients with multiple failures and multi-drug resistance (estimated at 8% of French patients) are an immediate treatment priority and new strategies currently being evaluated include treatment interruption and/or mega-HAART. Simply adding single new drug to a failing regimen risks quickly developing resistance to the new drug and is not recommended.
Recommendations:
Immunotherapy
Perhaps the most surprising inclusion in the guidelines is the section on immunotherapy. Encouraging results from recent IL-2 studies have led to recommend:
Primary infection
Preliminary studies of therapy in patients with symptomatic primary infection have shown that initiating treatment during this period is able to preserve HIV-1 specific immune responses.
Recommendations:
Metabolic abnormalities
It is noted that 50% of patients currently treated with antiretroviral therapy in France have reported varying degrees of lipodystrophy associated symptoms: abnormal distribution of body fat or metabolic abnormalities of glucose and lipid levels. It is recognised that the mechanisms responsible for these effects are not understood and that protease inhibitors are not the only responsible explanation.
Modification of treatment has not produced a high reported success rate in reversing these symptoms and optimal virological suppression should always remain a priority when regimens are changed in an attempt to limit or reverse lipodystrophy symptoms.
Recommendations:
Therapeutic drug level monitoring (TDM)
There is little indication for the use of TDM for NRTIs because of their reliance on phosphorylation. Greater individual PK variability associated with protease inhibitor plasma levels and the greater number of potential interactions with other medications though means that TDM provides important information with PIs.
Recommendations:
Recommendations:
Pregnancy in women infected with HIV
The use of combination therapy has increased the number of HIV-positive women who want to have children. The use of anti-retroviral treatment has reduced the risk of mother-to-child transmission to less than 5%. Symptoms that have been diagnosed as mitochondrial disease have been identified among children that have been exposed to anti-retroviral treatment during pregnancy. Prescription of anti-retroviral treatment therefore includes uncertainties.
The healthcare of HIV-positive pregnant women should be managed as a collaboration between her HIV doctor, obstetrician, paediatrician and the woman herself. Most cases of transmission occur at the end of pregnancy.
Recommendations:
Paediatric HIV infection
Initial treatment in children should follow the same principles recommended for adults. In children it is important to be particularly aware of:
Recommendations:
Co-infection with hepatitis viruses and HIV
The prevalence of hepatitis is high according to HIV exposure risk category. HCV infection is aggravated by HIV infection. 15-20% HIV-associated deaths in France are linked to HCV cirrhosis.
The guidelines recognise that care for patients co-infected with HIV and HBV/HCV is often not adequate. Treatments for hepatitis are effective but made more complicated by co-infection with HIV. One essential criterion for HCV treatment is stopping alcohol consumption.
Recommendations:
Opportunistic infections
Due to the successful restoration of the immune system following combination therapy:
Accidental and occupational exposure to HIV
Recommendations for PEP should be taken on a case by case basis taking into consideration type of exposure, severity of exposure and treatment history of the source of the infection, of known. Evaluation of risk of infection should not be limited to risk of HIV but broadened, for example, to include HBV and HCV
IVDUs and antiretroviral treatment
There are interactions between ritonavir, nelfinavir, nevirapine, efavirenz and methadone which lower the blood plasma concentration of methadone
The guidelines include a table of available drug interactions and recommendations for dose adjustments.
A reduction in methadone levels as a result on starting antiretroviral treatment can induce withdrawal reactions. There are fewer interactions with buprenorphine (Subutex).
Recommendations:
HIV-2
HIV-2 disease evolves more slowly than HIV-1. There is currently no available test to measure HIV-2 RNA.
Recommendation
Adherence Limitations of current treatment strategies are important and numerous: multiple agents, side effects, lifelong treatment, strict adherence requirements.
Recommendations
To prepare all patients carefully prior to starting any treatment and then to re-evaluate continuously the difficulties that the patient may have with their treatment.
Although the fifteen antiretroviral agents available now in the United States can be combined into an enormous number of drug regimens, the presence of extensive cross-resistance within the three approved classes limits the number of effective sequential combinations available to any one patient. When drug failure occurs, the effectiveness of the subsequent regimen will depend largely on the drugs used for prior therapy, the timing of the institution of the next regimen, and the choice of agents. Clinicians should also consider the reasons for drug failure: a patient who is non-adherent with a relatively simple initial combination is unlikely to do better on a second, more complex salvage regimen. Judicious use of resistance testing can also help guide the choice of agents. Clinicians should never prescribe antiretroviral therapy without considering what options will remain should those drugs fail. Now that HIV infection is a chronic disease, manageable for decades in many patients, it is crucial to think strategically when starting or changing antiretroviral therapy.
When to Modify Therapy
Virologic failure is typically defined as the failure to achieve adequate viral suppression (e.g., HIV RNA <40 c/ml within 20-24 weeks) or the rebound of detectable virus in a patient whose viral load had previously been undetectable. Although therapy continues to provide benefit as long as viral load is maintained significantly below baseline, there are two important reasons to consider changing early: durability and cross-resistance. The nadir of the viral load is a key predictor of a durable antiretroviral response [Kempf DJ, et al. AIDS 1998;12:F9-F14]. Only those who achieve the goal of undetectable virus using an ultrasensitive assay and continue compliance can be expected to experience a sustained antiviral effect. Furthermore, continued therapy despite ongoing viral replication leads to cross-resistance that may ultimately limit the effectiveness of future therapy. This is especially true for protease inhibitors, for which the amount of resistance and cross-resistance is a function of the cumulative number of resistance mutations.
The appropriate time to switch from a failing regimen depends on the types of drugs being used in the regimen, on the consequences of continued viral replication in the face of the selective pressure exerted by those drugs, and on the availability of reliable salvage options. With protease inhibitors, there is now evidence that patients are more likely to respond to a change in therapy if the change is made early when the viral load is still low [Hall CS, et al. AIDS 1999;13:1207-1212; Tebas P, et al. AIDS 1999;13:F23-F28; Hammer S, et al. Abstract 490, 6th CROI, Chicago, 1999]. This strategy limits the number of resistance mutations that result in cross-resistance within the protease inhibitor class. This may be less true for non-nucleoside reverse transcriptase inhibitors (NNRTIs), for which class-wide cross-resistance can occur following the development of a single mutation. For NNRTI-based regimens, early use of resistance testing may help to determine whether other drugs in the class will be effective. It is less clear whether early switching is necessary when patients fail nucleoside-based regimens (e.g. ddI/d4T/hydroxyurea or AZT/3TC/abacavir). Continued therapy with an AZT-containing combination following early drug failure might lead to more extensive AZT/3TC resistance or to multi-nucleoside resistance. The same may be true for d4T-containing regimens as well, although less is known about nucleoside resistance following d4T therapy.
Changing Therapy: Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs)
Cross-resistance among the nucleoside analogues remains poorly understood, but new data suggest that it is more extensive than had been previously appreciated. The M184V mutation, which leads to high-level 3TC resistance, is seen in many patients failing abacavir. Cross-resistance between those drugs is unidirectional: abacavir-resistant virus is resistant to 3TC, but virus resistant only to 3TC retains susceptibility to abacavir. However, abacavir is generally ineffective against virus with the M184V mutation and three or more AZT resistance mutations. In clinical trials abacavir has been shown to be ineffective as a salvage agent in patients with extensive NRTI resistance [Hammer S, et al. Abstract 490, 6th CROI, Chicago, 1999. Squires K, et al. Abstract LB-15, 6th CROI, Chicago, 1999]. The M184V mutation can be beneficial in some cases. In addition to decreasing viral fitness, it is known to enhance the activity of adefovir and to reverse or prevent the development of some AZT resistance mutations. However, patients taking AZT/3TC can develop specific mutations (e.g., mutations at codons 208, 211, 214, and 333) which render both drugs inactive.
Recent evidence suggests that mutations typically associated with AZT resistance can occur following failure of d4T in AZT-na•ve patients [Calucz, et al. 3rd Resistance Workshop, Rancho Bernardo, 1999]. Some experts have proposed that these mutations should be thought of as "thymidine analogue mutations" rather than "AZT resistance mutations." Obviously, these findings have major implications for our ability to use nucleoside analogues in sequence. However, more data are needed on the relative frequency of these mutations following d4T therapy as compared to AZT therapy.
Multi-drug resistance conferring cross-resistance to the entire NRTI class is now well recognised. Multi-nucleoside resistant genotypes include the Q151M resistance complex and the T69SSS insertion mutation. Isolates that carry multiple AZT resistance mutations along with the M184V mutation may also exhibit resistance to multiple nucleoside analogues. Most of the data on multi-nucleoside resistance comes from studies of AZT-treated patients. Less is known about the likelihood of developing cross-resistance after the use of other NRTI-containing regimens.
It has been suggested that NRTIs may sometimes fail for reasons other than genotypic resistance. For example, it has been proposed that prolonged AZT use impairs the subsequent phosphorylation of d4T, rendering it less effective [Sommadossi JP, et al. Abstract 3, 12th World AIDS Conference, Geneva, 1998]. However, other studies have found no such difference in phosphorylation [Phiboonbanakit D, et al. Abstract 487, 6th CROI, Chicago, 1999]. Furthermore, there is evidence that when d4T is used along with protease inhibitors, AZT-experienced patients have the same response as AZT-naive patients [Gallant JE, et al. AIDS 1999:13;225-229]. Another potential explanation for the diminished effectiveness of one NRTI after exposure to another involves the effect of resistance mutations on viral fitness. While AZT resistance mutations may lead to a decrease in viral fitness, subsequent compensatory mutations may actually increase viral fitness and lead to a diminished response to other nucleoside analogues [Keulen W, et al. Abstract I-111, 38th ICAAC, San Diego, 1998].
Thus, it is clear that second NRTI regimens may be less reliable than initial regimens for a variety of reasons. Whether there is a preferred order in which NRTIs should be sequenced has not been determined. Fortunately, clinical trials are now in progress that should help answer this important question. Resistance testing may be helpful in assessing the degree of nucleoside resistance and cross-resistance at the time of failure in patients failing initial drug regimens. Those with extensive NRTI resistance may require treatment with combinations that include both NNRTIs and protease inhibitors.
Changing Therapy: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Cross-resistance among the three currently available NNRTIs is extensive. The presence of the K103N mutation, a mutation seen frequently in patients failing delavirdine, nevirapine, or efavirenz, renders all three agents ineffective [Kemp, et al. 3rd Resistance Workshop, Rancho Bernardo, 1999]. Thus, it is unwise to deliberately set out to use NNRTIs in sequence. However, some patients failing nevirapine or delavirdine have resistance due to other mutations, such as Y181C, thereby retaining some susceptibility to efavirenz. In such patients resistance assays can be used to determine the susceptibility to efavirenz, provided they are performed while the patient is still taking the NNRTI. A number of new NNRTIs are in development that may be effective against virus carrying the K103N mutation and double mutants. For that reason, it may be wise to discontinue therapy with failing NNRTIs, since the accumulation of additional mutations may preclude the later use of these "second generation" agents.
There is evidence that patients on dual-PI combinations after failure of a single PI respond better to salvage therapy when an NNRTI is incorporated into the regimen [Deeks SG, et al. Abstract 22490, 12th World AIDS Conference, Geneva, 1998]. This reflects the likelihood of cross-resistance within the PI class and the fact that most patients failing PIs are also highly NRTI-experienced. Unfortunately, the effects of the three-way drug interactions in such combinations are unclear, and doses must be chosen without the benefit of good pharmacologic data.
NNRTIs are important in NRTI-experienced patients as well. In ACTG 364, a trial involving patients who were heavily NRTI experienced, participants failing NRTI therapy were randomised to receive nelfinavir (NFV), efavirenz (EFV), or NFV/EFV plus open-label NRTIs [Albrecht M, et al. Abstract 489, 6th CROI, Chicago, 1999]. Those randomised to receive both NFV/EFV appeared to have the best response to therapy, though there was no significant difference between the NFV/EFV and the EFV groups. Both arms did better than those on NFV and nucleoside analogues, for reasons that are unclear.
Changing Therapy: Protease Inhibitors
Unfortunately, cross-resistance within the protease inhibitor class is extremely common. The resistance patterns of indinavir and ritonavir are almost identical, and saquinavir resistance also leads to resistance to other PIs. Early resistance to nelfinavir and amprenavir usually occurs as a result of unique mutations (D30N and I50V, respectively), and in the case of nelfinavir, there are clinical data suggesting that patients failing nelfinavir often respond to other protease inhibitors [Tebas P, et al. AIDS 1999;13:F23-F28]. However, recent data suggest that a substantial proportion of patients develop resistance to nelfinavir as a result of alternate genotypic pathways, such as L90M, and that such patients are more likely to have cross-resistance to other PIs [Condra J, et al. 3rd Resistance Workshop, Rancho Bernardo, 1999].
Dual PI-regimens (e.g., RTV/SQV, RTV/IDV, NFV/SQV) are frequently used as salvage therapy after failure of an initial PI-containing combination. This approach has generally been associated with poor results in patients with indinavir resistance [Deeks SG, et al. AIDS 1998;12:F97-F102], although patients who begin the salvage regimen when their viral load is still low may have a better response [Hall CS, et al. AIDS 1999;13:1207-1212]. The data have been more encouraging in nelfinavir-resistant patients, as noted above. The role of amprenavir after failure of a first PI remains to be determined.
A number of studies have demonstrated the counterintuitive finding that patients failing PI-containing regimens may not always have PI resistance. In ACTG 343, a trial testing the induction-maintenance strategy, many patients failing indinavir monotherapy or triple-therapy with AZT/3TC/IDV had 3TC resistance (M184V) but no resistance to indinavir [Havlir D, et al. Abstract LB12, 6th CROI, Chicago, 1999]. Similar findings have been reported from the French Trilege trial [Descamps D, et al. Abstract 493, 6th CROI, Chicago, 1999] and in the Merck 054 and 067 trials [Holder DJ, et al. Abstract 492, 6th CROI, Chicago, 1999]. These findings support the concept of "intensification," discussed below, especially if resistance tests can be used during early failure to identify the drugs that should be changed and drugs that can be continued. However, currently available resistance assays are known to be insensitive to resistant mutants present in small quantities. We may be underestimating the amount of protease inhibitor resistance when we use resistance tests during early drug failure.
The Role of Intensification It is now clear that only patients who achieve an undetectable viral load using an ultrasensitive assay can expect a durable antiretroviral response [Montaner JSG, et al. Abstract 12364, 12th World AIDS Conference, Geneva, 1998.] However, completely changing a regimen that is "failing" by that rigid standard might lead us to exhaust our options prematurely. Several studies support the strategy of intensification, in which a HAART regimen is augmented with an additional agent or agents if the target goal is not reached [Mellors J, et al. Abstract 12295, 12th World AIDS Conference, Geneva, 1998; Gisolf EH, et al. Abstract 12274, 12th World AIDS Conference, Geneva, 1998]. "Intensification" usually refers to the addition of one or more drugs to a partially successful regimen: one which is suppressing viral replication but which has either not brought the viral load to undetectable levels using an ultrasensitive assay or which has resulted in low-level viral rebound following complete suppression. The potential problem with this approach, however, is that it is perilously similar to the addition of a single drug to a failing regimen, a now discredited practice that is responsible for a great deal of drug resistance. We cannot always rely on resistance testing to distinguish between a regimen that is failing and one that is "partially successful," since decisions about whether to intensify a regimen are frequently made before the viral load is high enough to allow these assays to be performed. For this reason, some intensification strategies may be safer than others from a resistance standpoint. For example, since it is not an antiretroviral agent, the addition of hydroxyurea to a ddI-containing combination may reduce viral load without increasing the risk of drug resistance. The addition of abacavir to an AZT/3TC-containing regimen may also be safe, since continued use of AZT/3TC would result in resistance mutations that would presumably preclude the use of abacavir in future regimens, anyway. Intensifying a single-PI regimen with ritonavir might improve efficacy because of enhanced pharmacokinetics or convenience. On the other hand, adding an NNRTI to a PI-based combination (or vice versa) risks development of resistance to multiple classes of drugs.
Other Antiretroviral Agents
A number of NRTIs, NNRTIs, and PIs are now in clinical trials or pre-clinical development, and many show promising activity against drug-resistant strains. These include the NRTIs lodenosine (FddA) and dOTC; the NNRTIs AG 1549, DPC 961 and 963, GW420867X, and (+)-calanolide A; and the PIs ABT-378, tipranavir, AG 1776, and BMS-232632, to name a few. ABT-378 is now being studied in large-scale clinical trials for the treatment of patients who have failed therapy with single PIs, and preliminary data look promising [Benson C, et al. 3rd Resistance Workshop, Rancho Bernardo, 1999]. In addition, several novel classes of antiretroviral agents are being studied, many of which may hold promise for patients with extensive resistance to NRTIs, NNRTIs, and PIs. The two classes that are farthest along in development are the nucleotide reverse transcriptase inhibitors and the fusion inhibitors.
The nucleotide adefovir is available now through an expanded access program and is used primarily in salvage therapy or intensification protocols. It has relatively modest potency and is inactive against virus with high-level AZT resistance. However, the M184V mutation increases activity by approximately 0.5, making it logical to co-administer this drug with 3TC. There is also synergy between adefovir and hydroxyurea. The originally tested dose of 120 mg daily was poorly tolerated because of a high incidence of nephrotoxicity, and trials are now ongoing using a daily dose of 60 mg. PMPA, a second nucleotide that appears to have greater potency than adefovir, is now in clinical trials.
T-20, the first fusion inhibitor, inhibits gp41-mediated membrane fusion between HIV and CD4 cell membranes. Because of its unique mechanism of action, there is no cross-resistance to any of the currently available drugs. It is given by subcutaneous injection and is generally well tolerated. In a phase II, dose-ranging trial, use of the highest dose (100 mg SC b.i.d.) was associated with a decline in viral load of 1.5 log [Lalezari J, et al. Abstract LB-13, 6th CROI, Chicago, 1999].
The Use of Resistance Testing
Genotypic and phenotypic resistance assays are now widely used. There is evidence from both retrospective and prospective studies that these tests can help us to design more effective drug regimens in experienced patients. However, while resistance assays are excellent predictors of drug failure, they are insensitive to resistant strains present in small quantities and are therefore somewhat less effective at predicting drug susceptibility. When resistance tests are ordered with the expectation that they will determine the best drug regimen, they are likely to give misleading information. These tests are frequently overused in patients who have been exposed to multiple agents in the past, in whom they invariably underestimate the amount of resistance resulting from prior therapy. On the other hand, they are under-utilised in patients failing early therapy, when they can provide extremely useful information about the type and amount of drug resistance that has developed. Appropriate indications for resistance testing include the following:
Management of the Patient with Limited Therapeutic Options
Clinicians treating HIV-infected patients are now faced with a large number of patients with extensive treatment experience and broad cross-resistance to the currently available agents. A number of approaches have been suggested for the management of such patients. "Recycling" involves the reuse of antiretroviral agents used in previous treatment regimens. While the re-use of drugs discontinued for reasons unrelated to resistance is acceptable, recycling of drugs used in failing regimens is generally discouraged since resistant mutants remain in small quantities long after the drugs have been discontinued. There may be some exceptions to this rule, however. 3TC may allow some patients to re-use AZT because of the reversal of some AZT mutations by M184. Hydroxyurea may sometimes overcome resistance to ddI. However, the effectiveness of these approaches in an individual patient is unpredictable, and they should never be viewed as completely reliable options.
"Mega-HAART" refers to the strategy of combining up to nine drugs in patients with extensive prior drug exposure and cross-resistance. This approach has a sound rationale: no matter how many drugs and drug combinations a patient has taken, it is unlikely that any one virion will be resistant to all of the drugs in a complex, multi-drug regimen. This approach may lead to significant reduction in viral load, at least in the short-term [Montaner JSG, et al. Abstract I-201, 38th ICAAC, San Diego, 1998; Workman C, et al. Abstract 22372, 12th World AIDS Conference, Geneva, 1998]. However, toxicity is high, and many patients are forced to discontinue mega-HAART regimens or a number of their components. Thus, while there may be a role for mega-HAART salvage therapy in highly motivated and adherent individuals, it is unlikely that this approach will be the answer to the problem of multi-drug resistance for most patients.
Based on a handful of preliminary reports, patients are expressing growing enthusiasm for "drug holidays." In one study a substantial proportion of patients who took a drug holiday prior to the initiation of mega-HAART salvage therapy experienced reversion of virus to wild-type [Miller V, et al. Abstract 030, 2nd International Workshop on Salvage Therapy for HIV Infection; Toronto, 1999]. Those with wild-type virus at the time of salvage therapy had better short-term responses to mega-HAART than those who maintained drug-resistant phenotypes. However, it is likely that re-emergence of resistant strains present at low levels will eventually lead to viral rebound. Furthermore, reversion to wild-type virus during drug holidays was associated with a greater decline in CD4 count, presumably because of the increased fitness of wild-type virus. It is reasonable to consider a drug holiday in patients who are experiencing significant drug toxicity, but it is premature to embrace drug holidays as a therapeutic strategy.
While the primary goal of antiretroviral therapy is maximal and prolonged suppression of HIV replication, it is clear that patients who have failed multiple antiretroviral agents have often exhausted all available options. In such patients it is unrealistic to strive for complete viral suppression, and little benefit is to be derived from frequent or early switches. The addition of single new drugs as they become available only serves to exhaust agents that could have been used in later combinations.
Fortunately, patients who continue HAART despite virologic failure often do well clinically and virologically for some time. While the CD4 count response may be blunted, the CD4 count frequently remains elevated long after the viral load has rebounded, and clinical progression appears to be slow [Kaufmann D, et al. Abstract 12101, 12th World AIDS Conference; Geneva, 1998; Deeks S, et al. Abstract 494, 6th CROI, Chicago, 1999]. This so-called "disconnect" between virologic failure and clinical and immunologic response may be explained by the decrease in viral fitness associated with some resistance mutations. Patients without effective treatment options may still benefit from continued antiretroviral therapy, provided the drugs being used are well tolerated and do not interfere with quality of life.
Conclusions
Because our currently available antiretroviral agents fall into three classes and have overlapping resistance patterns, the treatment of experienced patients remains enormously challenging. Fortunately, new drugs are becoming available that may be active against resistant virus. The use of resistance assays and the growing body of data from clinical trials will also help us to design better drug regimens for treatment-experienced patients. Ultimately, however, the best way to deal with the problem of drug resistance is to prevent it from happening in the first place. Ensuring access to expert care for all patients prior to starting antiretroviral therapy is an important first step. Patients should be provided with effective, well-tolerated, and convenient regimens only after they have been extensively counselled about the critical importance of strict adherence and have decided they are ready to start treatment. Finally, we must continue to approach antiretroviral therapy with strategies designed to promote long-term success. Our therapeutic goal, to provide decades of viral suppression and health, is ambitious but achievable. To reach this goal, it is critical that we think about the long-term implications of each decision we make.
Adapted from, "Antiretroviral Therapy in the Treatment-Experienced Patient," AIDS Reader, 1999;9(4):284-291. (c)1999. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Mary Beth Hansen, Managing Editor. Website: Johns Hopkins AIDS Service.
Source: The Hopkins HIV Report - September 1999 http://ww2.aegis.com/pubs/jhopkins/1999/JH990901.html
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ANTIRETROVIRALS
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Researchers at St. Jude Children's Research Hospital in Memphis, Tennessee, have found a possible explanation for why some HIV-infected patients who have no detectable drug-resistant strains do not respond to antiretroviral drugs. Dr. John Schuetz and colleagues conducted in vitro studies to investigate alternative or additional mechanisms to account for this lack of therapeutic response. Using a human line of T lymphocytes resistant to adefovir, they found that "...overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA (9-(2-phosphonylmethoxyethyl)adenine) [adefovir] and azidothymidine [AZT] monophosphate from cells and, thus, with resistance to these drugs."
"Overexpression of MRP4 mRNA and MRP4 protein severely impaired the antiviral efficacy of [adefovir, AZT] and other nucleoside analogues," they report in the September issue of Nature Medicine. "MRP4 is the first transporter, to our knowledge, directly linked to the efflux of nucleoside monophosphate analogues from mammalian cells."
"What we've been able to do is to show that there is a protein that will pump out the important active components of certain antiretroviral drugs. What we noticed was that the principal component of the drug was leaking out of the cell, and it was leaking out in a manner that suggested a pump." Using screening techniques and specific reagents, his group was able to identify that pump as the multiple drug resistance protein MRP4.
"We also have very preliminary data that there appears to be a variation among individuals in their peripheral blood monocytes." And while Dr. Schuetz believes that all individuals probably have the MRP4 protein, it is not yet clear how much variation in MRP4 levels there is among individuals.
Dr. Schuetz's group is currently in the process of evaluating HIV-infected patients in a clinical setting to confirm that overproduction of MRP4 protein correlates with lack of response to antiretroviral drug therapy. "Our next goal," Dr. Schuetz added, "...will be to try to identify specific [MRP4] inhibitors to increase [antiretroviral] drug effectiveness."
Source: Reuters Health. Ref: Nat Med 1999;5:1048-1051.
Patients with plasma HIV-1 RNA levels that cannot be quantified using the Amplicor HIV-1 Monitor system (<400 copies/mL), but that can be detected, have a much greater risk of virologic relapse.
Investigators from the University of North Carolina at Chapel Hill conducted a retrospective cohort study in which they evaluated the plasma HIV-1 RNA findings obtained during a 13-month period using the Amplicor HIV-1 Monitor.
Dr. Joseph J. Eron and associates identified 168 patients with HIV-1 RNA level <400 copies/mL who were stable on antiretroviral therapy. Their readings were further classified as "below quantifiable limits" or "below detectable limits." "Virologic relapse occurred in 52 of 168 individuals over 29,576 person-days overall (incidence rate 1.8 cases/1,000 person-days)," they report in the July 30th issue of AIDS. The virologic relapse rate was three times greater among the subjects with below-quantifiable limits compared with those with below-detectable limits.
"After adjusting for baseline CD4 cell count, number of antiretroviral medications, and use of [protease inhibitor] and/or [nonnucleoside reverse transcriptase inhibitors], the rate of relapse was nearly four times greater for individuals with HIV-1 RNA levels [below quantifiable limits]."
Dr. Eron's group stresses that the findings "...should be interpreted with caution." The results obtained in their laboratory using the Amplicor HIV-1 Monitor "...may not be generalizable to other methods of measurement or to the same method applied in other laboratories." Nevertheless, they believe that these results "...emphasise that suppression of HIV-1 RNA to the lowest level possible should be the goal of antiretroviral therapy." In addition, Dr. Eron's group observed an independent effect of CD4 cell count on virologic relapse, which "...suggests a role for the host immune response in controlling viral replication and breakthrough on antiretroviral therapy."
The findings also show that "...all HIV-1 RNA results <400 copies/mL are not equivalent," indicating a "...role for enhanced-sensitivity assays in the routine monitoring of antiretroviral therapy in selected patients."
Source: Reuters Health. Ref: AIDS 1999;13:1337-1342.
Hydroxyurea (HU) increases the action of other anti-HIV drugs - even against viral strains resistant to those drugs, a new study suggests. HU, an anticancer agent of long standing, inhibits the cellular enzyme ribonucleotide reductase and leads to reduced pools of deoxynucleotide triphosphates (dNTPs). Reduced pools of dNTPs favour HIV uptake of nucleoside analogue inhibitors of HIV reverse transcriptase.
As the most pronounced reduction of dNTP is among deoxyadenosine triphosphates (dATPs), Stanford researchers Sarah Palmer and colleagues explored the synergy between HU and three adenosine-based nucleoside-analogue reverse transcriptase inhibitors (NARTIs): didanosine (the already approved ddI or 2'-3'-dideoxyinosine); PMEA (9-[2- (phosphonylmethoxy)ethyl]adenine); and PMPA ((9-[2- (phosphonylmethoxy)propyl]adenine).
They found that HU not only increased the drugs' anti-HIV activity, but that it increased the activity of ddI and PMEA against ddI- and PMEA-resistant HIV mutants. "This study provides evidence that supports the need for clinical trials with HU in combination with ddI against ddI-resistant patient isolates and in combination with two recently developed adenosine analogues, PMEA and PMPA," Palmer et al. wrote.
Source: Aegis Ref: Palmer et al. Antimicrobial Agents and Chemotherapy. 1999;43(8):2046-50). Ref: AIDS 1999 Aug 20;13(12):1477-83
Abstract
Background: After the initial discovery of 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and thione (TIBO) derivatives, several other non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), including nevirapine (BI-RG-587), pyridinone derivatives (L-696,229 and L-697,661), delavirdine (U-90152), alpha-anilinophenylacetamides (alpha-APA) and various other classes of NNRTI have been described. The hallmark of NNRTI has been based on their ability to interact with a specific site ('pocket') of HIV-1 RT.
Objective: To investigate whether, in addition to HIV-1, different strains of HIV-2 (ROD and EHO) and SIV (mac251, agm3 and mndGB1) are sensitive to a selection of NNRTI i.e. delavirdine, the HEPT derivative I-EBU (MKC-442), 8-chloro-TIBO (tivirapine), alpha-APA (loviride), nevirapine and the pyridinone derivative L-697,661.
Methods and Results: The NNRTI tested inhibited the replication of the different strains of HIV-2 and SIV at micromolar concentrations. The inhibitory effects of the NNRTI on HIV-2-induced cytopathicity correlated well with their inhibitory effects on HIV-2 RT activity. Drug-resistant HIV-2 (EHO) variants containing the Ser102Leu and/or Glu219Asp mutations in their RT were selected after passaging the virus in MT-4 cells in the presence of increasing concentrations of delavirdine. The EHO virus mutants were at least 20-fold less susceptible to the antiviral effects of delavirdine. Some cross-resistance, depending on the mutant strain, was observed with the other NNRTI tested (i.e. MKC-442, tivirapine, loviride and pyridinone L-697,661).
Conclusions: Our data demonstrate that NNRTI are not exclusively specific for HIV-1 but are also inhibitory to different HIV-2 and SIV strains. These observations will have important implications for the development of new NNRTI with higher activity against both HIV-1 and HIV-2. Furthermore, in view of their anti-SIV activity, NNRTI could be evaluated further for their in vivo anti-retrovirus efficacy in non-human primate models.
Ref: Witvrouw M, Pannecouque C, Van Laethem K, et al. AIDS 1999 Aug 20; 13(12):1477-83.
Nevirapine (Viramune) suspension has now been approved for use in children over two months in the UK but will have no impact on NHS drug budgets until the next financial year as part of Boehringer Ingelheim's continued commitment to the management of HIV drug budgets, the company announced today. Viramune is the first oral suspension belonging to the NNRTI (non-nucleoside reverse transcriptase inhibitors) class to be approved for children over two months.
Dr Gareth Tudor-Williams, Consultant in Paediatrics at St Mary's Hospital, London welcomed the news. "In our experience nevirapine provides an excellent therapeutic option for many of our patients, being effective, usually well tolerated and of paramount importance in children, very palatable which improves adherence."
Adverse event data for nevirapine treated patients aged two months to 19 years indicate that nevirapine is generally well tolerated. Based on experience of 361 paediatric patients treated in clinical trials, the most commonly reported adverse events include rash, fever, nausea, fatigue, headache, somnolence, vomiting, diarrhoea, abdominal pain, myalgia and abnormal liver function tests. Granulocytopenia is a paediatric specific adverse event. Severe and life-threatening skin reactions and hepatotoxicity, including fatal cases of each have occurred in adult patients treated with nevirapine tablets.
Source: Boehringer Ingelheim press release.
Abstract
Objective: Despite advances in antiretroviral treatment, a large number of HIV-infected patients still require hospitalisation. This study describes the characteristics of HIV patients requiring hospitalisation before and after the advent of potent antiretroviral therapies.
Methods: Information was collected on all HIV-positive patients admitted to the New York Hospital - Cornell Medical Center in New York City. Data was collected from 1 January through 30 June 1995, and during the same 6-month interval in 1997.
Results: In each time period over 1500 outpatients were receiving treatment for HIV infection. There was a significant decrease in the incidence of admission [60.4 per 100 patient-years (PY) in 1995, 28.8 per 100PY in 1997], and length of stay (10 versus 8 days). The median CD4 cell count of all HIV-infected patients admitted to the hospital doubled: 37(106/l in 1995 versus 80(106/l in 1997. However, there was no significant change in the median CD4 cell count of patients diagnosed with opportunistic infections. The incidence of the most common diagnosis (bacterial pneumonia, 8.0 per 100PY in 1995 versus 3.6 per 100PY in 1997) and the most common opportunistic infection (Pneumocystis carinii pneumonia 7.6 per 100PY in 1995 versus 2.4 per 100PY in 1997) decreased significantly.
Conclusions: Since the introduction of potent antiretroviral therapy, a significant decrease in the incidence of hospital admission and opportunistic infections has occurred. There has been a doubling of the median CD4 cell count of inpatients. There has been no significant change in the median CD4 cell count at which patients present with opportunistic infections.
Ref: Paul S, Gilbert HM, Ziecheck W. AIDS 1999, 13:415-418.
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PATHOPHYSIOLOGY
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Investigators studied the effect of highly active antiretroviral therapy (HAART) on 113 patients with the CCR5 delta 32 mutation. The CCR5 delta 32 allele is found primarily among whites. In the study, a treatment regimen that included an HIV-1 protease inhibitor was given to white patients with CCR5wt (wild type)/delta 32 and those with CCR5wt/wt. Virologic success was defined as a plasma HIV-1 RNA level of under 400 copies/mL at the last clinic visit. The researchers found that 81 percent of the CCR5wt/delta 32 subjects and 57 percent of the CCR5wt/wt patients experienced virologic success after HAART. According to the data, the patients with CCR5wt/delta 32 experienced a greater rise in median CD4 cell counts than those with CCR5wt/wt. The investigators concluded that white patients with CCR5wt/delta 32 are probably more likely to achieve virologic success and higher CD4 cell counts after initiation of HAART than those with CCR5wt/wt.
Ref: Valdez, Hernan; Purvis, Scott F.; Lederman, Michael M.; et al. Journal of the American Medical Association (25/08/99) Vol. 282, No. 8, P. 734. Source: CDC HIV/STD/TB Prevention News Update
European researchers report an increased number of drug-resistant primary HIV-1 infections in the August 28 issue of The Lancet. The investigators studied 82 antiretroviral-naive individuals with primary HIV-1 infection between 1996 and 1998 at the Geneva AIDS Centre. According to the research, 9 percent of the subjects were zidovudine-resistant, primary-resistance mutations associated with protease inhibitors occurred in 4 percent of patients, and 11 percent had viral variants resistant to one or more antiretroviral drugs. The researchers concluded that resistance testing should be conducted early on in HIV infection in order to provide the best antiretroviral treatment.
Source: CDC HIV/STD/TB Prevention News Update
Abstract
Objective: To investigate the optimal time point for the initiation of therapy in HIV infection from the perspective of drug resistance.
Background: The enormous genetic diversity of HIV within an infected individual represents one of the greatest challenges for effective therapy, because the viral population may harbour drug-resistant mutants that rapidly outgrow the wild-type virus once the patient starts treatment. To determine the optimal timing of therapy it is crucial to know how long it takes for the viral population to build up sufficient diversity to enable the virus to escape from therapy.
Method: A stochastic model of the viral diversification during primary infection was used to study the behaviour of small population sizes of mutant virus.
Results and Conclusions: The simulations suggest that from the perspective of viral diversity, therapy should be started at the viral set-point. Starting treatment earlier involves a risk of the selective outgrowth of drug-resistant mutants, which are transiently present at the viral peak during primary infection.
Ref: Ruy M. Ribeiro & Sebastian Bonhoeffer. AIDS 1999, 13:351-357.
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IMMUNOLOGY
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In a phase III study of 309 patients with late stage AIDS, adding Leukine (sagramostim) for 6 months to a stable HAART regimen, leads to better viral load and immune improvements when compared to a HAART plus placebo group. The Leukine arm also required fewer changes in their HAART regimens than the placebo arm. The results add to the weight of evidence that adding immune modulating therapy to HAART will improve outcomes.
While the advent of HAART (highly active antiretroviral therapy) has revolutionised the treatment for HIV, not all patients respond and many develop drug-resistant HIV strains. There is a leading theory and some evidence that adding some type of immune modulating therapy to HAART will improve outcomes. One example of this is Proleukin (aldesleukin, interleukin-2).
Now, researchers from five clinical centres in North America have reported adding another white cell growth factor to HAART. They used Leukine (sargramostim, GM-CSF or granulocyte-macrophage colony stimulating factor). Leukine is an FDA-approved drug to boost white cell production after chemotherapy for leukaemia or after organ transplantation. Prior to the advent of HAART, researchers were reluctant to use Leukine for HIV/AIDS patients due to concerns of increasing HIV production by stimulating growth of white cells that are reservoirs for the virus.
Patients in the study had a T cell count of 50 cells per microliter or less, or 100 cells per microliter or less with a history of a prior AIDS-defining illness. All were taking a stable HAART regimen for at least 29 days and preventive therapy for opportunistic infections. The 309 patients were stratified into 2 groups by baseline HIV viral load: greater than or less than 30,000 copies per milliliter. The group was then randomly assigned to taking either placebo or Leukine injections under the skin, 250 micrograms 3-times weekly, for 24 weeks. The study was double-blind, meaning that neither the patients nor their physicians knew whether drug or placebo was being administered. During the study period, physicians were allowed to change their patients' HAART regimens, based on viral load endpoints.
Using a strict "intent-to-treat" analysis (all patients initially enrolled are included in the analysis), 70% completed 24 weeks. Leukine was tolerated well, with mild skin injection site reactions. The results showed that the Leukine group had a significantly higher CD4 cell percentage increase (31% increase) than the placebo group (0% increase). The absolute CD4 counts (not percentage) increased from a median baseline of 51 to 94 cells per microliter in the Leukine arm. Whereas, the increase in the placebo arm was from 50 to 71 cells per microliter.
A greater percentage of patients with a baseline undetectable HIV viral load (less than 400 copies per milliliter) remained undetectable at 24 weeks (83%) than the placebo arm (54%). In a sub-analysis of patients with an entry CD4 count between 50-100 CD4 cells per microliter, those in the Leukine arm had significantly fewer changes in their HAART regimens than those in the placebo arm.
Even though this study had a group of more severe AIDS patients, based on CD4 counts and/or prior AIDS-defining illnesses, there were no significant differences at 24 weeks in cumulative opportunistic infections, time to first AIDS event or death. The incidence (rate of new) of opportunistic infections in the Leukine group was 67%, compared with 78% in the placebo group.
An optional, blinded extension of the study continued up to 20 months of treatment. A total of 45% of patients participated. Among the 115 patients who did so and who had a baseline viral load less than 30,000 copies per milliliter, 81% of the Leukine arm had no HAART change and maintained an undetectable viral load. Whereas, only 62% of patients in the placebo arm had no HAART change and remained with an undetectable viral load.
The authors concluded that when Leukine is added to a stable HAART regimen in late-stage AIDS patients, each of the following occurs: greater CD4 cell count increases, a higher percentage maintains HIV viral load undetectability, and fewer changes in HAART are required. Another phase III study will be necessary before FDA approval could be sought. There are no reported trial results of Leukine plus HAART in patients with higher baseline CD4 counts.
Refs: Angel J and others. Randomised, double blind, placebo-controlled study of sargramostim (yeast-derived GM-CSF) in advanced HIV disease: significant improvements in CD4 and viral load. The Canadian Journal of Infectious Diseases 1999:10(B), 26B and abstract B223 at the Eighth Annual Canadian Conference on HIV/AIDS Research, May 1999. AIDS Compendium, Leukine maintains viral suppression in AIDS patients. Infectious Disease News 1999 July, 44-45. Source: HIV&Hepatitis.com, 18/08/99.
Abstract Cellular immune responses are thought to be an important antiviral host defence, but the relationship between virus-specific T-helper and cytotoxic-T-lymphocyte (CTL) responses has not been defined. To investigate a potential link between these responses, we examined functional human immunodeficiency virus type 1 (HIV-1)-specific memory CTL precursor frequencies and p24-specific proliferative responses in a cohort of infected untreated persons with a wide range of viral loads and CD4 cell counts. Levels of p24-specific proliferative responses positively correlated with levels of Gag-specific CTL precursors and negatively correlated with levels of plasma HIV-1 RNA. These data linking the levels of HIV-specific CTL with virus-specific helper cell function during chronic viral infection provide cellular immunologic parameters to guide therapeutic and prophylactic vaccine development.
Ref: Kalams SA, Buchbinder SP, Rosenberg ES, et al. J Virol 1999 Aug;73(8):6715-20.
Abstract
Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38(+) activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.
Ref: Kalams SA, Goulder PJ, Shea AK, et al. J Virol 1999 Aug;73(8):6721-8
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MISCELLANEOUS
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The first patient with concomitant HIV and hepatitis B virus (HBV) infection received a liver transplant nearly 3 years ago at King's College Hospital in London. The group has now performed liver transplants in five patients with HIV infection. Those without concomitant hepatitis C infection are showing relatively long-term survival after transplantation.
"In the past, we did not consider [HIV-positive patients] candidates for liver transplants. Over the past 3 to 4 four years, antiretroviral treatment has changed the prognosis...we can now expect survivals of 10 to 15 years," Dr. Nigel D. Heaton told Reuters Health during the Fifth Congress of the International Liver Transplantation Society in Pittsburgh.
Two patients with HIV and HBV are showing survival rates approaching 3 years, Dr. Heaton reported. His group attempted liver transplantation in another 3 patients with concomitant HIV and hepatitis C infection. All three of these patients have died, with the longest surviving just under 3 years. "We didn't see HIV progression in these patients," Dr. Heaton said. "They died of complications of HCV."
Dr. Heaton noted that "...we have effective antiviral treatments for both HBV and HIV. I think we can expect to see significant increases in survival [after transplantation in this group]." For patients with HIV and HCV, Dr. Heaton said his group is making modifications in immunosuppressant regimens in an effort to improve survival.
"Probably steroids are not good and we have tried to eliminate steroids. More important might be the timing of anti-HCV treatment, with more aggressive pre-and post-treatment regimens. We're moving toward pre-emptive treatment with ribavirin and interferon and getting the HIV infection under control."
Many of the patients with HIV who might be candidates for liver transplantation are young, Dr. Heaton noted. Many are in their early 30s with families. "Achieving a survival of 10 to 15 years is important for watching those families grow up."
Source: Reuters Health.
A Swedish transplant surgeon reported Friday at the 5th Congress of the International Liver Transplantation meeting in Pittsburgh that the HIV protease inhibitor nelfinavir appears to greatly reduce the clearance of the immunosuppressant tacrolimus.
The adverse effect was seen in an HIV-positive haemophilic who underwent liver transplantation for hepatitis C-related cirrhosis. "We saw a very strong interaction" with tacrolimus when nelfinavir was reintroduced 2 weeks postoperatively, Dr. Gunnar Soderdahl of Huddinge Hospital in Sweden, told Reuters Health in an interview during the meeting.
Blood levels of tacrolimus were so elevated that Dr. Soderdahl had to decrease the dose to 0.5 mg once a week. "The usual dose is seventy times higher than that," he noted.
The high serum levels of tacrolimus caused a slight increase in serum creatinine levels but did not cause significant nephrotoxicity and levels returned to normal after the tacrolimus dose was cut back. The patient has not experienced any acute rejection episodes with the reduced tacrolimus regimen. Nelfinavir's action appears to be unimpaired, the Swedish physician reported.
The patient is currently experiencing a recurrence of hepatitis C virus infection, and Dr. Soderdahl is considering putting the patient on a combination of ribavirin and interferon. He says that he will watch for possible drug interactions with these agents and tacrolimus, as well.
Dr. Soderdahl explained that nelfinavir, tacrolimus and ribavirin all use the same cytochrome p450 3A4 metabolic pathway. "We expected an interaction," he said, "but we didn't expect it to be this dramatic."
Source: Reuters Health.
A baby at high risk of having HIV will have to be tested for the virus even though her parents oppose it following a landmark ruling in the High Court. The move has massive implications for parents' rights to decide what treatments their children should have. The girl - who cannot be named for legal reasons - is four months old and her mother is HIV positive. Her parents believe in the effectiveness of alternative medicine and say it has kept the mother healthy so far. They had said they feared they would lose control over the way the child was treated if the test goes ahead. But Camden Council said the baby could die if she is also HIV positive and goes untreated, and wants the child to receive the highest standard of medical treatment available.
Source: BBC Online
Intrapartum and Neonatal Single-Dose Nevirapine Compared with Zidovudine for Prevention of Mother-to-Child Transmission of HIV-1 in Kampala, Uganda: HIVNET 012 Randomised Trial A multicentre team of researchers has found that nevirapine reduced the risk of HIV-1 transmission by almost half during the first 14 to 16 weeks of life in a breastfeeding population. More than 600 HIV-1-infected women at Mulago Hospital in Kampala, Uganda, were studied. The women received either nevirapine at the onset of labour, with a dose given to their infants within three days of birth, or zidovudine administered throughout labour and delivery, with twice daily doses administered to their infants during the first week of life. Virtually all the babies were breastfed, and about 95 percent were still breastfeeding after 14 to 16 weeks. In the zidovudine and nevirapine groups, the estimated risks of HIV-1 transmission were: 10.4 percent and 8.2 percent, respectively, at birth; 21.3 percent and 11.9 percent at six to eight weeks; and 25.1 percent and 13.1 percent after 14 to 16 weeks. According to the researchers, "Single-dose nevirapine given to the mother and the baby is likely to be one of the few deliverable and sustainable strategies for prevention of perinatal HIV-1 transmission in resource-poor settings."
Ref: Guay, Laura A.; Musoke, Philippa; Fleming, Thomas; et al. Lancet (04/09/99) Vol. 354, No. 9181, P. 795. Source: CDC HIV/STD/TB Prevention News Update
To determine the cost effectiveness of the HIVNET 012 single-dose nevirapine regimen as a way to reduce perinatal HIV-1 transmission, researchers used a hypothetical cohort of 20,000 pregnant women in sub-Saharan Africa. The primary outcome measures were program cost, number of paediatric HIV-1 cases averted, cost per case averted, and cost per disability-adjusted life year (DALY). Under most plausible scenarios, the HIVNET 012 regimen costs between $5 and $55 per DALY, with base-case estimates of $5.25 to $19.18 per DALY. According to the authors, the drug regimen--in which single-dose nevirapine is administered to mothers and infants intrapartum period and soon after birth--can be extremely cost-effective in high seroprevalence areas. Furthermore, the researchers note that in lower seroprevalence areas, where multi-dose treatments are not routinely used, "nevirapine therapy could have an important public-health impact at a reasonable cost."
Ref: Marseille, Elliot; Kahn, James G.; Mmiro, Francis; et al. Lancet (04/09/99) Vol. 354, No. 9181, P. 803. Source: CDC HIV/STD/TB Prevention News Update