11th Conference on Retroviruses and Opportunistic Infections: Treatment Report
This year's 11th Conference on Retroviruses and Opportunistic Infections (CROI), held in San Francisco in February, continued to provide us with new information on how to best combine -- or perhaps more often, not combine -- antiretroviral combinations; new agents in development; important information on older meds, especially as they are applied in the developing world settings and; complications of long-term HAART (highly active antiretroviral therapy). We will hit the highlights of these topics as well as some important socio-political-economic issues in both this country and across the world.
This is not headline stuff anymore, but there was further data presented through the Tonus study, Landman, et al., that supported last summer's surprise findings regarding the triple-nuke combo tenofovir + abacavir + 3TC. This study again showed an extremely high percentage of virologic failure (12/36, 33%). Eleven of the 12 had virologic failure with the K65R and the 184V mutations, 1/12 only had the 184V. Then there was the Jemsek, et al., data that showed miserable results with tenofovir, ddI and 3TC. Same story, different channel; 20/22 participants experienced virologic failure. 91%. No one reached <50 copies. Ouch! 10/20 (50%) had the K65R and 184V mutations, 10 had the 184 alone. In both studies, those with viral loads >100,000 at baseline had the worst outcomes. The table below compares data from these two trials presented at CROI as well as the ESS3009 from last summer.
All of these data do mean that we have ample clinical trial evidence that triple-nuke therapy is not a good idea; and that some combinations are disastrous. There are ongoing clinical trials evaluating whether starting therapy with a more intense, potent regimen, then backing off to Trizivir® might be a valid therapeutic approach. Do we know that answer yet? NO. Should you and your doctor be playing around with such an approach before the clinical trial data is in? We don't think so. There are so many viable, tolerable regimens out there these days. It is much wiser to wait for the data, being gathered in a controlled setting, than to be practicing cowboy medicine in this age of choices.
Elion et al. presented data from the COL40263 study that looked at once-daily Trizivir® + tenofovir (Viread®) in antiretroviral-naive individuals. The early results are less than stellar. With 8-week data on 88 participants, 78% of those on treatment had viral load (VL) <400, 67% <50. For those with a baseline VL >100,000, only 60% reached <400. Granted, it's early data, but it doesn't look too promising. These data are no more promising that Trizivir® alone and beg the question why bother with the fourth drug, especially when there seems to be a high level of toxicity-related drop-outs (22%). The most interesting thing to emerge from this study so far is that of 8 virologic non-responders, only 1 person developed the K65R mutation. It appears that AZT prevents the development of the K65R. So what's up with this K65R mutation? Read on.
The K65R mutation is new to many of our HIV vocabularies. It is a nucleoside reverse transcriptase-associated mutation selected by the nukes abacavir (ABC, Ziagen®), ddI (didanosine, Videx), d4T (stavudine, Zerit®) and tenofovir (TDF, Viread®). The triple nuke data above speaks to the risk of "popping" the K65R, especially in sub-optimal combos like TDF, ABC and 3TC. There you have 2 drugs that select for the K65R and 3TC which has the signature mutation M184V. So, there's a lot of hype out there about the K65R. Depending on one's pharmaceutical bias, or lack thereof, there has been widespread panic, or the downplaying of significance. In an attempt to see through the industry hype, there are some very interesting aspects to this little-known, but growing in prevalence mutation.
There are at least two ways in which nucleoside mutations can cause resistance: decrease binding or incorporation and increased excision. When nucleoside analogues work, they are incorporated into the cell-blocking reverse transcriptase from being able to assist HIV in its replication process. Incorporation is good. It means the drug is getting where it needs to be. Decreased incorporation is bad.
Excision is the process by which the drug(s) in question are removed (excised) from their proper place of work -- booted out. Excision is bad. Decreased excision is good. Whew -- this is complicated stuff.
The K65R seems to decrease incorporation of most nukes (this is bad), but also, with some drugs, decrease excision (this is good). For tenofovir, abacavir and ddI decreased incorporation caused by the K65R appears to leads to at least a partial decrease in drug susceptibility. With d4T, the resistance jury is still out. Of interest however, with AZT, the K65R decreases incorporation, but also decreases excision to such a point that it outweighs the negative effect of decreased incorporation. It actually appears to make the K65R mutant virus more susceptible to AZT. It also appears to reverse pre-existing AZT resistance. You could visualize it as:
Tenofovir, ddI and abacavir and the K65R mutation: decreased incorporation + increased excision = decreased susceptibility (this is not so good).
AZT and the K65R mutation: decreased incorporation + decreased excision = increased susceptibility (this is good!).
D4T and the K65R mutation: decreased incorporation + decreased excision = ?? the jury is out.
Got that? We'll look more at incorporation and excision in a future issue of Resolute! It's fascinating though, don't you think?
There were several presentations that addressed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and their signature mutation, the K103N. There are currently three FDA-approved NNRTIs: efavirenz (Sustiva®), nevirapine (Viramune®), and delavirdine (Rescriptor®). The most commonly used are efavirenz and nevirapine, two drugs that have low pill counts, are very strong and have long half lives, making them easy to take and easy to combine with NRTIs. In the past couple of years, nevirapine has also been used in the developing world to prevent MTCT (mother-to-child transmission), with just one pill to mom during labor, and one to the baby after delivery. The results have been similar to the long-standing short-course AZT therapy used during labor and delivery. With all of this in mind, let's look at the data presented at CROI concerning these drugs and the K103N mutation.
The K103 Sticks Around and Does Not Effect Replicative Capacity
Little et al. presented data after following 10 individuals for 3 years who were infected with NNRTI-resistant HIV. These individuals had HIV virus that replicated very well (84% of wild type) and there was a very slow and incomplete reversion of their virus to wild type. What does this mean? This data in conjunction with the data from Palmer et al., which showed the persistence of NNRTI mutations even when the drugs have been removed, gives strong evidence that NNRTI resistance is long lasting and does not effect replicative capacity. (Unlike some other mutations, associated with NRTIs and PIs, that reduce HIV's ability to replicate.)
What's the real-world, take-home message? Efavirenz and nevirapine are highly effective antiretroviral medications that, when used in combination with other medication and when very well (high level of adherence) can lead to very long-lasting combos. However, when NNRTI resistance occurs, it sticks around and does not effect the "fitness" of the K103N mutant virus.
Single-Dose Nevirapine Leads to Development of the K103N Mutation
Martinson, et al. presented data that showed the emergence of the K103N and other NNRTI-associated mutations with just one dose of nevirapine. Six hundred twenty three HIV-infected mothers received nevirapine (NVP) before delivery; their infants were given NVP within 72 hours after delivery. Four hundred fifty six women and children were followed for 7 weeks after delivery. Almost 40% of the women were found to have NVP resistance. The transmission rate to infants was 8.6%. 42.4% of the HIV-infected infants also had NVP resistance. There was increased risk for NVP resistance developing with higher viral load and lower CD4 count. Muro et al. supported these findings by giving 200 HIV-negative women single-dose NVP and then tracking how long the drug stayed measurable in their blood. The median half life measured was 56.7 hours (with the range being 25.6-164 hours!). The time to "undetectability" (when no drug could be measured) ranged from 11 days to >22 days. The implication of this study supports the emergence of resistance from single-dose nevirapine because it hangs around in the blood so long.
The obvious question is, should we be giving single-dose NVP to pregnant women in the developing world? Not if we want to be able to use those drugs later. Considering that the World Health Organization's combo pill made from generic drugs contains nevirapine, the answer is a resounding NO. Could we, however, give two other antiretroviral meds for a couple of weeks following delivery to "cover the nevirapine tail?" Perhaps. It will need to be studied.
Adding Nevirapine to Short-Course AZT During Labor and Delivery Lowers MTCT Rates
In another study, by Lallemant et al., short-course AZT monotherapy to mother and child was compared to AZT + NVP. The study was double blinded, placebo controlled. There was a placebo arm in which no NVP was given. This arm was stopped because there was such significant difference this arm and the NVP-containing arms. The results were impressive. The transmission rate dropped from approximately 6.3% (in the stopped placebo arm) to 2% and 2.8% in the continuing arms. This brings the perinatal transmission rate down to close to that of what women on HAART therapy are experiencing in the US. Once again, transmission was associated with higher viral loads and lower T-cell counts.
In a sub-study of ACTG 5095, Ribaudo et al. looked at correlating efavirenz (EFV) concentrations with race, discontinuation, CNS toxicity, and viral load response. One hundred ninety subjects were available for analysis: 19% women, 32% African American, 15% Hispanic. What did they find? Race, it turns out, was strongly associated with EFV clearance. African Americans and Hispanics cleared EFV slower than whites. In fact, white folks cleared EFV from their system 32% faster. There appeared to be no association between how fast EFV cleared and hepatitis C coinfection (good news). There was an increase in discontinuation of EFV with slower clearance. In other words, the longer the drug hung around in people, the more likely they were to quit taking it. However, this study showed no association between slower clearance rates and increased central nervous system (CNS) side effects. (Say what? This doesn't make sense to this treatment advocate -- it makes me wonder how they defined CNS side effects and why these folks discontinued the drug?). There was no association between EFV clearance and how well it suppressed HIV (that's good news).
In another study where Haas et al. tried to get at why EFV concentrations are higher in some folks, there was an association with the presence of a polymorphism called the CYP2B6 G516T (it's a particular manifestation of a liver enzyme). This polymorphism is more frequent in the African-American population, and may explain why EFV concentrations are higher, and clearance slower in African Americans. In this study, presence of the CYP2B6 G516T was associated with increased CNS side effects. There were no apparent differences in virologic or immunological response.
These findings are significant and must be followed up with further analysis. They speak to several issues on the minds of those living with HIV and those treating HIV infected individuals. One is, people are not paper cut-out dolls. We come in differing sizes, genetic make-up, hormonal influences and who knows what else. We cannot go into the future treating every PLWH/A like they will react the same to these meds. We need therapeutic monitoring of the drugs that we can monitor easily NOW. In this world of inequalities, it is especially important that racial differences be followed up and understood. The barriers to treating disenfranchised communities are too large to have only a little information on medication differences. This is fascinating information and if appropriately followed, could lead to reducing the side effects of efavirenz in some individuals, while maintaining its potency. That would be great!
Gathe, et al., presented 48 week data from a open label study that compares lopinavir/r (Kaletra®) once-daily (QD) to lopinavir/r twice-daily (BID). Participants in both arms also took FTC (emtricitabine/Emtriva®) and tenofovir (Viread®). The virologic results are impressive. The QD arm performed as well as the BID arm, with the only statistical difference being the amount of diarrhea experienced in the QD arm. The results are below.
Our CROI coverage has really concentrated on the here and now. Just like you, our readers, we are very interested in the drugs coming down the pike. The closer to approval, the more effect it has on our daily lives, but the more novel the targets, the more hope there is for the future. Rather than go into the details of all of the new drugs in development, I'd like to just report this:
We currently have 20 licensed antiretroviral medications. At a recent CROI update, Steve Johnson, M.D., eloquently summarized what characteristics new medications being developed should have: more potency, fewer pills, fewer side effects, less drug-drug interactions, effective against resistant virus, and useful in pregnancy. At this year's CROI there were reports on: 10 entry inhibitors; 3 NRTIs; at least 6 NNRTIs; 1 PI; and 1 maturation inhibitor. That's 21 new agents that were presented. There are far more in development. What does this tell us? The pipeline is alive and well. Some of the new drugs are aimed at new targets. In the next issue of Resolute! we'll look at these new targets, including: CCR5, CXCR4, budding, attachment, integrase ...
Within the next year, we will most likely see: tipranavir, a new protease inhibitor; abacavir-3TC combined formulation; tenofovir-FTC combined formulation; and new formulations of d4T, nelfinavir, saquinavir and lopinavir-ritonavir.
This article was provided by PWA Coalition Colorado. It is a part of the publication Resolute!.