Tuesday, November 28, 2023
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Editor's Note:
The balancing act between efficacy and tolerability has become increasingly complex as new antiretroviral agents are introduced
and used in sequence to address the treatment needs of individual patients. At the 3rd IAS Conference on HIV Pathogenesis
and Treatment, July 24-27, 2005, in Rio de Janeiro, Brazil, Scott Williams, Program Director, Medscape HIV/AIDS and Infectious
Diseases, interviewed Ian Sanne, MD, Director of the Clinical HIV Research Unit, University of the Witwatersrand, at the Helen
Joseph Hospital in Johannesburg, South Africa, about the challenges posed for selecting regimens in treatment-experienced
patients, and how those challenges are magnified in resource-constrained settings.
Medscape: Many HIV clinicians are now using ritonavir-boosted protease inhibitor (PI) regimens for their treatment-experienced patients, most commonly atazanavir (Reyataz), fosamprenavir (Lexiva), lopinavir (Kaletra), or saquinavir (Invirase). When HIV clinicians prescribe one of these agents for treatment-experienced patients, what are the most pertinent factors related to efficacy and tolerability that influence drug selection?
Dr. Sanne: Certainly the level of resistance mutations and particularly PI resistance mutations would be the first determining factor. The first PIs that would be considered would be atazanavir, lopinavir, and saquinavir -- all of them preferably ritonavir-boosted. In principle, given the level of resistance mutations, the different PIs will respond differently. That would be the first factor in the choice. The potency -- viral efficacy -- is similar between the 3 drugs. And then tolerability becomes the more pertinent issue, in particular gastrointestinal (GI) disturbances -- mostly abdominal pain and diarrhea. Next, the long-term side effects of elevated proatherogenic lipids and metabolic side effects including glucose metabolism and glucose tolerance need to be considered. It appears as though there are some benefits to atazanavir -- even ritonavir-boosted atazanavir over lopinavir/ritonavir. . The mechanism of these benefits is unclear as yet.
Atazanavir is associated with less insulin resistance as measured by the development of syndrome X, according to data presented at previous conferences.[1]
The additional concern that seems to be coming through now is the concomitant use of omeprazole[2] (Prilosec) and ranitidine (Zantac).[3] In this area, the investigational PI, TMC-114, appears to have a benefit because it can be used with omeprazole.[4] The reason this is important is because up to 50% of the patients use over-the-counter proton-pump inhibitors [PPIs] intermittently, and so this may actually become an issue in the future. At this meeting, new data were presented on the interaction of atazanavir with proton-pump inhibitors (PPIs).[5] In one study, coadministration of atazanavir and omeprazole resulted in lower levels of atazanavir. However, good clinical and virologic outcomes were documented in 2 retrospective clinical trials[6,7] of patients who took PPIs along with atazanavir. Once multidrug-resistant viruses have emerged with multiple mutations, then it's the newer classes of drugs, and agents in the existing classes with activity against drug-resistant HIV, that are coming through, particularly TMC-114.[8] The concomitant use of T20 [Fuzeon; enfuvirtide], however, provides significant benefit over the use of TMC-114 alone. That appears to be the trend going forward; as we have seen with tipranavir/ritonavir, it is important to have other active drugs in the regimens, even for PIs with activity against highly drug-resistant virus.[9]
Medscape: The US Food and Drug Administration (FDA) approved a new PI, tipranavir (Aptivus), in the last couple of months. Tipranavir clearly fills an important role in salvage therapy, but one of the concerns with the safety is that of hepatotoxicity in HIV and hepatitis B- or C-coinfected patients. How must clinicians use the drug in HIV and hepatitis-coinfected patients who have fewer remaining HIV treatment options?
Dr. Sanne: The identification of hepatitis is the first step -- seeking out hepatitis B and C and then the early monitoring for toxicities associated with tipranavir. In principle, unless it's grade 3/4 toxicity, we'd probably recommend treating through. Clearly, there's a risk for severe dose-limiting hepatotoxicity, with the potential of hepatic failure. We want to avoid that by regular monitoring.
Medscape: We've talked a little about standard boosted PIs, but what about double-boosted PI regimens? These are being used in some clinics for highly treatment-experienced patients, but there really is minimal prospective data on a lot of these combinations. What advice do you have for clinicians who choose to enlist these novel regimens, and what looks good so far in your opinion?
Dr. Sanne: Dual PIs, boosted with ritonavir, is a treatment option for patients who have failed first-line treatment and cannot use nucleosides because of toxicity. There are a variety of ways of combining these. The atazanavir/saquinavir combination is being tested. It appears to be useful in its overlapping antiviral efficacy. In principle it would be most interesting to actually combine atazanavir and lopinavir My advice would be that if this is the second regimen and if it's needed because of toxicity and NNRTI [nonnucleoside reverse transcriptase inhibitor] failure, any 2 compatible PIs can be used in a dual-boosted PI regimen. In deep salvage therapy there is a body of evidence in crossover studies that the addition of 2 PIs may be beneficial. It's interesting at the moment because the newer agents are still coming through, but once the new agents -- such as tipranavir, but also the investigational agent TMC 114 -- become more easily accessible, we'd probably go with the single-boosted PI.
Medscape: What about tenofovir (Viread) and didanosine (Videx) in treatment-experienced or salvage patients? We're all aware of the data of concern over the past year or 2 that have come out regarding those 2 medications.[10-14] What dosing is appropriate, and how should patients be monitored if these drugs do need to be combined in treatment-experienced or salvage patients because of resistance, or possibly because they can't tolerate other agents?
Dr. Sanne: I'm still a great friend of ddI [didanosine], especially the enteric-coated formulation used in salvage patients. The tenofovir/didanosine combination clearly is a problem because of the drug interaction resulting in lowering of the tenofovir dose. In deep salvage therapy, it would be advisable to try and stay away and rather use 3TC [Epivir; lamivudine] instead of ddI. In addition, it should be noted that the combination of didanosine/tenofovir/NNRTI is not recommended for use in treatment-naive individuals according to a recent update to the US Department of Health and Human Services (DHHS) Update.[15]
However, going back to didanosine, the interesting thing about ddI is that it's still active in the presence of the M184V mutation and it's also more likely to be active in the presence of thymidine analog mutations (TAMs). An important issue for patients is that you still need to dose ddI separate from the PIs in a multidrug regimen, which makes the regimen very complex to take. You have to take ddI on an empty stomach and you have to take PIs with a meal. So you can end up taking medicine 5 times a day. If there's no other choice, then that's what you have to do.
Medscape: You delivered a very elegant talk[16] at this conference on antiretroviral sequencing to maximize second-line and presumably salvage options in more resource-limited settings. In the developing world right now many resources have been directed at fixed-dose combinations and reduced cost regimens for initial antiretroviral therapy. In a resource-limited country such as South Africa, what are the best current options for second line and possibly salvage when these first-line combinations fail?
Dr. Sanne: The interesting thing about South Africa is that we have a relatively good government tender price on lopinavir/ritonavir, and therefore we have used Kaletra as the second-line therapy and as the first PI for the national roll-out program. It is combined with didanosine, which means that we have, again, the separation of ddI on an empty stomach and then the PI. The ddI is, in fact, still the buffer-coated, not the enteric-coated ddI, so people are ending up taking that twice a day. I think that in the near future it will become interesting to see whether atazanavir could potentially replace lopinavir/ritonavir with the added advantage that one could then push lopinavir/ritonavir out into salvage therapy.
Medscape: Would you use the atazanavir boosted?
Dr. Sanne: I use unboosted atazanavir because of the simplicity of it, the lack of refrigeration. An important question that has not been studied as yet is which should be the first PI following the first-line treatment using an NNRTI regimen. A comparative study of atazanavir (boosted or unboosted), lopinavir/ritonavir, and even saquinavir/ritonavir should be undertaken. Atazanavir on its own has acceptable efficacy. Once that fails, then you use lopinavir/ritonavir. We've had no need as yet because it's a young national rollout program, and there's no drug procurement plan by the government to purchase salvage drugs. In essence what we are doing is resistance testing and then piecing together a regimen out of the 6 drug options that we have. Tenofovir ends up as a potential salvage drug that we can purchase at the referral sites. More wide-scale use in the national roll-out plan will depend on pricing. Ideally, we would rather use tenofovir up front, and that's my current argument -- that we use it first and leave ourselves the thymidine analogs for second-line treatment and potential recycling of those drugs in salvage. But we're ending up using tenofovir in salvage treatment, probably not the most efficient use.
