Salvage Therapy

Ritonavir+Indinavir. What is salvage therapy? After a person develops resistance and drug failure to potent drugs such as a protease inhibitor or NNRTI, it can be difficult to find a regimen that works effectively. That is a situation where people need salvage therapy. At this time, the double protease combination of ritonavir+indinavir appears to be an effective option for people who've failed protease inhibitor therapy, when combined with other drugs. At Retrovirus, a study was by reported by Mike Youle showing it to be a potent salvage therapy. In a small study, heavily pre-treated (extensive prior treatment experience) people who failed protease inhibitors received indinavir+ritonavir with a NNRTI, hydroxyurea+ddI and 1 or 2 NRTIs (a total of 5-7 drugs). After 24 weeks, 65% had undetectable viral load (<400 copies/ml). Ritonavir+indinavir appears to be an important component to consider including in a salvage therapy. Previous research had explored using indinavir+ritonavir in a dosing regimen of 400 mg twice daily of both drugs. Using that dosing regimen in preliminary research, individuals who had previously failed indinavir or saquinavir (we don't know their resistance profiles) showed profound viral load reductions in preliminary studies. Youle started his study participants on a 400/400 regimen but reported switching them to a regimen of 800 mg indinavir+100 mg ritonavir twice daily for each drug.

At Retrovirus, Merck researchers reported preliminary findings from exploring 3 dosing regimens of these 2 drugs in a small study with 8-10 individuals in each arm. It remains uncertain which might be the preferable dosing regimen. If taking the 400/400 dosing regimen, Merck researchers reported significantly higher blood levels (AUC and Cmin) of indinavir than if taking the standard dose regimen of indinavir (800 mg every 8 hours), however, the peak or Cmax remains the same. The key for the success of this 2 drug combination is the substantial increase in indinavir AUC and Cmin when combined with ritonavir. Using 800/100 or 800/200 every 12 hours resulted in much higher blood levels of indinavir than if using the 400/400 dose regimen. Using the 800/100, the AUC of indinavir increases 66% and the Cmin increased almost 10-fold compared to when using the 400/400 regimen. The AUC and Cmin of indinavir increase even more when using the 800/200 regimen. Using the 800/200 regimen, the Cmin doubles the Cmin using 800/100 and increases the AUC about 1/3. As a result Merck is now beginning pilot studies using the 800/100 dose regimen for treatment-naïve individuals, and using the 800/200 regimen for indinavir failures. In each of the 3 dose regimens, the previous eating restrictions for indinavir are lifted. But, Merck recommends continuing the hydration requirement of drinking at least 50 ounces of water per day. Using the 400/400 regimen has not yet been reportedly associated with increases in kidney stones. It remains to be seen if the high blood levels of indinavir seen with the 800/100 or 800/200 dose will cause increased incidence of kidney stones. The peak or Cmax does increase substantially using the 800/100 or 800/200 over when using the 400/400. It remains uncertain whether kidney stones are due to high Cmax or daily AUC. For more details and PK data, see Indinavir+Ritonavir article on the NATAP website.

Doctors are sometimes using what is called Mega-HAART (highly active antiretroviral therapy) regimens for difficult to treat individuals. These are individuals who have failed and have resistance to a number of different drugs. Mega-HAART is a combination of 5 or more drugs. The idea is that each drug may offer limited antiviral activity but added together the multiple drugs will hopefully supply the needed antiviral activity to reduce viral load to undetectable. By using resistance testing it may be possible to reduce the number of drugs used in the regimen by possibly identifying which drugs may or may not be effective for a person.

V. Miller and colleagues reported at Retrovirus on a small study suggesting that a drug holiday may have increased the antiviral activity of drugs used in a mega-HAART salvage therapy regimen. Ten of 37 individuals receiving 6 or more drugs (mega-HAART) achieved and sustained viral load of <500 copies/ml; 8 were called partial responders (achieved but did not sustain undetectable viral load), and 6 did not reach undetectable. Median follow-up is 8 months. Seven of 10 responders and 2/8 partial responders were treated with a minimum of 4 sensitive drugs suggesting that resistance testing may be useful. The investigators said that drug holidays of 2-3 months resulted in a shift to a wild-type susceptibility and wild-type genotype and were associated with reduced viral load. In other words, virus resistant to drugs became sensitive to those drugs after a 2-3 month drug holiday. These findings are unexpected because it was thought that resistant virus would reemerge upon restarting therapy. Investigators also reported that virological response could be attained in patients with highly resistant viruses.

Resistance Testing. There are 2 types of resistance tests: genotypic and phenotypic tests. Using resistance testing may provide help in selecting drugs for a regimen. Evidence from recently reported studies is mounting that both types of resistance testing may help identify drugs one is sensitive to. Experts think that resistance testing is better at detecting the drugs to which a person is resistant rather than the drugs to which a person is sensitive. At the Retrovirus Conference the results of the GART Study showed that individuals who used the results of a genotypic resistance test in addition to expert advise on how to interpret the results had much better viral load reductions than individuals who did not use genotypic test results. Expert advice was offered by researchers/virologists at interpreting genotypic test results and using them to select a new regimen for a person. After 8 weeks individuals using genotypic test results along with expert advice had a viral load reduction of at least 1.17 log, while those who did not use genotypic test results in their treatment selections had a viral load reduction of .62 log. In addition, not everyone who received the genotypic test results took the expert advice. Those who actually made treatment decisions using the expert advice had viral load reductions greater than 1.17 log.

A Swiss research group including Luc Perrin and Bernard Hirschel conducted genotypic testing for reverse transcriptase (RT) and protease mutations in 62 individuals with viral load failure on HAART (viral load >1000 copies/ml). Patients had been treated for 35 months with NRTIs and 12 months with protease inhibitors. Median baseline CD4 count was 113 and viral load was 144,000 copies/ml. Although the subjects did not do particularly well overall in suppressing viral load with their new regimens, the number of genotypic mutations at baseline was predictive of the outcome. The new regimen was nelfinavir + new NRTIs. The median decrease in viral load was only 0.38 log and 32% had >1 log reduction in viral load. At baseline, 90% of participants had NRTI mutations with an average of 4 mutations (range 0-7). Primary protease mutations were detected in 69% and secondary protease mutations were detected in 89% of patients. The average number of PI mutations were 4 per person (range 0-9). The less NRTI, primary PI and secondary PI mutations a person had the better of a viral load reduction they achieved.

Recent studies of phenotypic resistance testing have shown similar results in improving the ability to select more effective regimens. However resistance testing technology is in its infancy and it is widely agreed that additional studies are needed to confirm how effective using these tests will be, and how to best use the results.

But, if you are in a situation now where you need to select a new regimen using resistance testing may provide help. Using both tests is probably preferable but expensive, as insurance reimbursement may be spotty. Resistance test providers are lobbying state Medicaid and private insurers to reimburse for the costs.

No Protease Inhibitor Resistance Detectable After Viral Load Rebound? Two separate reports at Retrovirus said that when individuals failed (viral load rebound) a regimen of indinavir+AZT/3TC , 3TC resistance was detectable but not indinavir resistance when resistance testing was used. This had previously been reported to have been observed for individuals taking either indinavir or amprenavir, a new PI from Glaxo Wellcome (see amprenavir article). The study investigators have suggested that if a person's viral load rebounds from undetectable when on a PI regimen a resistance test should be performed. If resistance to the PI is not detected, the person should consider remaining on the PI but changing the other drugs (for example changing 3TC or 3TC and AZT). In one study both phenotypic and genotypic resistance tests were performed. The study investigators suggest that 3TC resistance emerges first because it is easier for the virus to develop the 3TC resistance mutation (M184) because this mutation does not significantly reduce the ability of the virus to reproduce itself. As you may know, 3TC resistance develops quickly and the development of only one 3TC mutation (M184V) can cause high-level 3TC resistance. A few alternative explanations for not detecting PI resistance after viral load rebound have been offered. It has been suggested that indinavir resistance may be present at low levels, so it is not detectable, but might emerge later. Two other explanations are that the person may not be taking the PI, or they may not be achieving adequate blood levels of the PI in order to suppress virus replication .

In any case, I suggest being cautious in applying these findings when making treatment decisions. If a person is taking indinavir+AZT/3TC and their viral load rebounds after being undetectable, and 3TC resistance is detected but no indinavir resistance is detected, intensification can be considered. Rather than stop taking indinavir you might consider adding ritonavir at a dosing combination of indinavir 400 mg bid+ritonavir 400 mg bid. This would increase the indinavir blood levels appreciably. It increases indinavir Cmin 10-fold and AUC about 60% without increasing the Cmax (see amprenavir article on page 10 for explanation of AUC, Cmax and Cmin). A second option is to add delavirdine which also increases indinavir blood levels but it doesn't increase the Cmin as much as ritonavir does.

Transmission of Drug Resistant Virus. Two studies were reported at Retrovirus on their findings of transmission of resistant virus. The incidence of resistance to NRTIs detected in these studies is not higher than expected or previously seen. Some questions are raised by the high-level incidence of resistance seen to NNRTIs. As well, there are some questions about the levels of resistance seen to nelfinavir. S Little, from University of California at San Diego, reported on a study in which phenotypic and genotypic resistance testing was performed on 69 subjects with primary or acute HIV infection from 5 cities (San Diego 38, LA 6, Dallas 2, Denver 10, Boston 13). The individuals were evaluated from April '96 to July '98. They estimated that blood samples were obtained an average of 79 days (range 0-239) after estimated infection or 29 days after the first HIV+ test result. Individuals with >7 days prior therapy were excluded. 90% of the study participants were men. The average CD4 count was 548 and viral load was 83,000 copies/ml. Phenotypic resistance was divided into 2 categories: moderate resistance (2.5-10 fold decrease in sensitivity); major resistance (>10 fold-1000 fold decrease in sensitivity).

The percentage of individuals with any level of resistance (reduced sensitivity) to 1 or more of the NRTIs was 3%. In contrast the proportion of patients with reduced sensitivity to 1 or more NNRTIs was "surprisingly high at 14% , given that the use of the NNRTIs was not widespread at the time this study was conducted", Little said. The degree of reduced sensitivity (resistance) in these patients was typically lower than has been described in patients with phenotypic resistance. Interestingly, 22/23 samples with NNRTI resistance were from San Diego. Little said she plans further evaluation of these NNRTI findings. The percentage of patients with any level of reduced sensitivity to protease inhibitors-3% for saquinavir , 3% for indinavir, 6% for ritonavir, 10% for nelfinavir, and overall 13% of study participants had reduced sensitivity to 1 or more protease inhibitors. Little said there is significant natural variability in the sensitivity of wild type virus to the NNRTIs and nelfinavir, which may explain the high percentage of reduced sensitivity to NNRTIs and nelfinavir in this study. This suggests that the detected resistance to NNRTIs and nelfinavir may not be due to transmission of resistant virus. It's suggested that the high incidence of NNRTI resistance in both studies could be due to pre-existing resistance mutations in a person (also called polymorphisms) and not necessarily due to transmission of resistant virus. Polymorphisms do not necessarily led to actual resistance.

Little said it is of great concern that three patients (4%) in this study had a major reduction to 1 or more of the drugs tested. One person, from San Diego, had a 4-20 fold reduction in sensitivity to NNRTIs. The second patient from Los Angeles had a 12 fold reduction in sensitivity to AZT, and a 4 to 120 fold range in reduction to the different protease inhibitors tested. The third patient from Boston had a 9 fold reduction in sensitivity to AZT, >300 fold resistance to 3TC and he was the only patient from outside San Diego with any reduced sensitivity to 1 of the NNRTIs with a 6 fold reduced sensitivity to nevirapine. As the patient from LA this patient from Boston had a range in reduced sensitivity of 5 to 45 fold to the protease inhibitors tested.

For those with a moderate reduction in sensitivity they observed numerous polymorphisms, but no primary drug resistance mutations. Little said this suggests these are wild-type virus with reduced sensitivity of unknown clinical significance. This suggests to me that transmission of resistant virus in this case may not be the cause for resistance detected in vitro, in this study. In contrast, for those individuals with a major reduction in sensitivity, drug resistance mutations to AZT (T215Y) and 3TC (M184V) were detected. In the protease gene, 4 primary resistance mutations were seen-L90M, M46I, V82T, I84V-in the background of numerous secondary mutations. For the 1 patient with up to 20-fold reduced sensitivity to NNRTIs, no primary resistance mutations were seen. But, they saw numerous base pair substitutions in the binding pocket of reverse transcriptase which probably accounts for the reduced sensitivity of this patient.

Two subjects had reduced sensitivity to all 4 protease inhibitors. Reduced sensitivity to one drug (n=20) or more than one drug (n=7) was found in 28% of individuals. Reduced sensitivity to 2 or more classes of drugs or multi-drug resistance was present in 3% of subjects, with 1% having resistance to all 3 classes of drugs. Little concluded by suggesting that the incidence of resistance in acute infection may increase with earlier use of HAART. She continued--because there may be no exposure history to suggest the transmission of multidrug resistance this might suggest there is no basis for a more selective use of resistance testing; therefore, routine resistance testing in all cases of primary HIV infection may be crucial in selecting an optimal regimen in newly infected individuals.

G Wagner, with the US Military Research Program, reported that genotypic testing was able to accurately predict the presence of phenotypic resistance, except in the case of protease inhibitors where the genotype may have been more sensitive than the phenotype (at least in this group of treatment-naïve patients). The incidence of resistance to 2 different classes of drugs was 3.2% by genotype and 2.2% by phenotype. The incidence of resistance to all 3 classes of drugs was 2.1% by genotype and 3.3% by phenotype. Phenotypic resistance (>10 fold) was found to be 1% for NRTIs, 7.7% for NNRTIs, and 1% for PIs.

New Protease Inhibitors For Salvage Therapy. Several new protease inhibitors which are at various stages of development may be effective for individuals resistant to the currently available protease inhibitors. BMS-232632 is about to enter large scale human studies and will be the first protease inhibitor taken once a day. It may prove to be beneficial in salvage situations due to a unique resistance profile. A cross-resistance study involving 5 other protease inhibitors indicated that BMS-232632 resistant viruses show only partial cross-resistance to other protease inhibitors. Viruses resistant to other protease inhibitors retain sensitivity to BMS-232632. These findings are from in vitro studies, which although promising will have to be explored and confirmed in human studies. Until these confirmatory trials are conducted it is premature to draw conclusions. It appears as if this new PI does not interact as much with the p450 liver enzyme system as other PIs which if true, might mean potentially less drug-drug interactions to be concerned about.

ABT-378 is currently in small human studies and appears to be very potent. In a small study reported on at Retrovirus, 93-95% of treatment-naïve individuals had <400 copies/ml and 89% had <50 copies/ml after 24 weeks, using an On-Treatment analysis. Using an Intent-To-Treat analysis, 75% (24/32) had <50 copies/ml. See the NATAP website for more details on this study. The baseline viral load was about 100,000 copies/ml. ABT-378 will be combined with a small amount of ritonavir because it greatly enhances the blood levels of ABT-378. Although the resistance profile of ABT-378 appears partially different than for other PIs and has some overlapping resistance mutations, it appears to be promising for individuals with resistance to currently available PIs because of the high blood levels the drug can achieve when taken with ritonavir. Trough concentrations of ABT-378 with ritonavir are 25-100 fold above the IC50. This compares to about 4-fold for ritonavir and other PIs. ABT-378 will be co-formulated in 1 capsule containing 400 mg with 100 mg of ritonavir. So far, it appears to be more tolerable than ritonavir, and can be taken with or without food.

One study exploring ABT-378 in individuals who have previously failed one protease inhibitor is currently in progress. In study 765, a small number of individuals with a low baseline viral load, on average of about 10,000 copies/ml, received ABT-378 with nevirapine plus two NRTIs. The results are promising and will be presented this Summer. Large scale studies for FDA approval are about to begin. This will include a study for individuals with prior PI experience but who are NNRTI naïve. Additional trials are planned for individauls with prior PI and NNRTI experience.

Tipranavir has shown, from a few early small studies, that it may be effective for individuals with resistance to currently available protease inhibitors. In vitro studies showed tipranavir suppressed viruses containing mutations that cause resistance to currently available protease inhibitors. Further studies to explore tipranavir's usefulness as salvage therapy are needed and should start soon. As well, large scale studies for FDA approval will begin soon. Ritonavir appreciably increases tipranavir blood levels (AUC 20-fold, Cmin 40-50 fold) and when the two drugs were used together it appears to be tolerable. So, combining tipranavir with a small amount of ritonavir will be explored in studies. The most common tipranavir related side effects so far reported are GI related.

Amprenavir may receive FDA approval by the time you read this newsletter. It has a different resistance profile and may be useful for individuals with resistance to currently available PIs (see article on amprenavir, page 10). Some studies are in progress using amprenavir in salvage situations with individuals who have failed other protease inhibitors.

Monitor Viral Load Closely. If a person is developing resistance to their first PI, it is urged that they consider stopping the PI immediately, under the supervision of a physician. This is an important factor to bear in mind, because remaining on a PI while replication is ongoing, may allow resistance mutations to accumulate. The presence of many resistance mutations might prevent a person from responding to any of the new PIs discussed above.

A recent development complicates this decision (see page 5: No Protease Inhibitor Resistance Detectable After Viral Load Rebound?). Monitoring viral load every 4-6 weeks allows you to see viral load rebounds early enough to make quick changes. However, it is a different situation when a person has already used two or more protease inhibitors. If a person has failed or developed resistance to more than one or several PIs as is frequently the situation today, an immediate switch off the current PI is a more complicated decision.

T-20: first fusion inhibitor. T-20 works differently than currently available drugs. PIs, NNRTIs and NRTIs inhibit HIV reproduction after the virus enters a CD4 cell. T-20 prevents HIV from entering the CD4 cell. Important new information regarding T-20 was announced at Retrovirus. Early research with T-20 suggested that it could only be administered by infusion from a pump similar to how insulin can be delivered to diabetics. This would not be convenient. At Retrovirus, we heard early results from a study showing that T-20 can be effectively delivered by subcutaneous injection and still retain its antiviral activity. In a small one month study exploring several doses reported on at Retrovirus, T-20 reduced viral load by about 1.5 log when used at the highest dose. In fact, using subcutaneous injection was more effective than using the pump.

Since fusion inhibitors are a new class of drugs, T-20 is expected to be fully effective for individuals with resistance to or who have failed currently available classes of drugs-protease inhibitors, NNRTIs, NRTIs. As is the case with all antiviral drugs for HIV, T-20 will have to be used as part of a multiple drug combination because resistance can develop. The data from the study reported at Retrovirus suggested that resistance developed relatively quickly. However, researchers said after Retrovirus that viral load rebounded for individuals with over 100,000 copies/ml but not much for individuals with less than 100,000 copies/ml. Also, 41% of study participants received T-20 as monotherapy. In order to inhibit viral replication and prevent resistance it is necessary to suppress viral load to <50 copies/ml or as low as possible. A multiple drug combination is the most effective way to accomplish that. Trimeris (the developer of T-20) is planning a follow-up study to begin this Summer. The focus will be how to use T-20 in salvage situations. Trimeris is developing a second generation fusion inhibitor. In vitro and animal data on this second inhibitor showed it suppressed T-20 resistant virus and was more potent than T-20. The NATAP web site contains several articles offering a more lengthy discussion about T-20, including a more detailed report on the study presented at Retrovirus, and color illustrations of how T-20 inhibits fusion. In an unusual situation, manufacturing facilities capable of large-scale production will have to be developed because T-20 is the first of its type. The capacity to meet demand may not be ready in time for FDA approval. It could take a year after approval for supply to meet demand.

New NRTIs. Several new NRTIs are in early human studies, and may also offer assistance to individuals who have failed currently available NRTIs. The currently approved NRTIs include AZT, d4T, 3TC, ddI and ddC. Abacavir was approved by the FDA this past December. The new NRTIs may not be fully cross-resistant to the NRTIs that have been in use for a while. These new drugs include BCH-10652, FDDA, DAPD. Studies will explore if these new NRTIs are effective for individuals with extensive prior NRTI experience and resistance. DAPD may also be useful in treating hepatitis B. In preliminary in vitro studies DAPD was reported to be active against viruses from patients with resistance to AZT, 3TC or double resistance to AZT and 3TC. As well, DAPD was also fully active against virus with multi-drug resistance (the 69 S insertion mutation). An additional new NRTI called FTC is cross-resistant with 3TC, but it is more potent than 3TC and will be taken taken once-a-day, and also appears useful in treating hepatitis B. At Retrovirus, new antiviral activity of FTC from a 12 day monotherapy dose study was reported which explored 4 different doses. Baseline viral load was about 25,000 copies/ml and CD4 ranged from 406 to 464. After 12 days, the 200 mg once daily dose had the best antiviral activity with a peak in reduction of viral load of about 1.7-1.9 log at day 12; about 58% had either a >2 log decrease in viral load or <400 copies/ml., which was a higher percentage than other dose groups. This dose will be used for development.

FddA (lodenosine) shows little in vitro cross-resistance with other NRTIs and is active against multi-drug resistant HIV strains with the Q151M mutation. It will be tested for dosing twice daily and once daily because it has a long intracellular half-life (about 20 hours). In a preliminary monotherapy dose-ranging study in which 20/26 participants had >6 months NRTI experience with generally a variety of NRTIs, the average decrease in viral load was -0.42 log (range ­1.26 log to +0.38 log) at week 6 using lower doses of FddA. Higher doses are being tested and should provide more antiviral activity. At doses tested so far, some but not all heavily pre-treated individuals have responded to FddA monotherapy. In 7 patients studied there was no evidence of resistance mutations, so resistance may be difficult to develop, as it is with ddI. The authors of the report at Retrovirus said so far in short-term studies all doses have been well tolerated.

Adefovir and PMPA. Two once-a-day nucleotides (adefovir & PMPA) do not appear to be cross-resistant to other drugs and should provide help in salvage therapy. PMPA appears to be potent. Adefovir has modest potency and also appears to be active against hepatitis B. However, after using adefovir at a dose of 120 mg once daily for at least 6 months kidney-related lab abnormalities were emerging at rates of 22% or 32% (two seperate studies) of study participants that necessitated either reducing the dose or discontinuing the drug to resolve the lab abnormalities. In order to address this concern Gilead Sciences, the manufacturer of adefovir, has been studying a reduced dose of 60 mg once daily to see if that would reduce the kidney-related side effects while maintaining the drug's antiviral activity.

On March 19, at the 12th International Conference on Antiviral Research in Jerusalem, Gilead researchers reported results of studies comparing 60 mg to 120 mg of adefovir. In study 420, treatment-naive individuals received 60 mg adefovir monotherapy for 4 weeks. A mean decline in viral load of -0.25 log. was reported. In study 417, 211 protease inhibitor naïve individuals but who received prior treatment with multiple NRTIs received either 60 mg or 120 mg of adefovir in combination with either nelfinavir+saquinavir or a combination of a NRTI (AZT,d4T, or 3TC) with nelfinavir or saquinavir. The average prior AZT experience was about 90 weeks. Baseline viral load was about 31,000 copies/ml. After 20 weeks of this 48 week study, by an Intent-To-Treat analysis, 41% receiving 60 mg of adefovir had <400 copies/ml; and, 33% in the 120 mg arm had <400 copies/ml. Gilead reported that by week 20 there were 29 discontinuations in the 120 mg group vs 13 in the 60 mg group. About one-half of the 29 discountinuations in the 120 mg group were reportedly due to dose dependent GI related side effects such as nausea. By an On-Treatment analysis, 48% in the 60 mg arm had <400 copies/ml, and 45% in the 120 mg arm had <400 copies/ml. The kidney related side effects have been measured by changes in several lab tests-serum creatinine and phosphate. Using a Kaplan-Meier estimate to project changes in these lab tests after 42 weeks in this study, Gilead said the abnormality in the serum creatinine test improved from 42% in the 120 mg arm having > 0.5 mg/dL to 29% in the 60 mg arm. They also reported that decreases in serum phosphate to less than 2.0 mg/dL occurred in 26% in the 60 mg arm compared to 49% in the 120 mg arm.

Gilead researchers reported on the cross-resistance of 12 viruses resistant to NRTIs, adefovir, and PMPA which were assembled from patient blood samples The resistant viruses fell into 3 categories (all had 3TC resistance M184V mutation)- (1) low level AZT resistance (K70R mutation), (2) high level AZT resistance (T215Y/F+others), (3) multi-drug resistance (Q151M +other mutations). This study provided additional in vitro evidence to previous studies showing that in the presence of 3TC resistance both adefovir and PMPA may gain additional antiviral activity in humans. The 3 viruses with multi-drug and 3TC resistance were fully sensitive to adefovir. Two of the 3 Multi-drug resistant (MDR) resistant viruses were fully sensitive to PMPA. To one of the 3 MDR resistant viruses PMPA had almost 3-fold resistance (2.8-fold increase in IC50), which may too little a change in resistance to be relevant. Study researchers said that patients with MDR/3TC resistance will respond to adefovir or PMPA. So far in human studies resistance to adefovir appears difficult to develop. In vitro the K65R and K70E mutations cause resistance but in human studies these mutations have not yet been seen.

At Retrovirus, investigators from ACTG 359 reported unexpected preliminary PK results from a small study looking at PI combinations, delavirdine and adefovir in various combinations. Adefovir appeared to decrease delavirdine AUC (blood levels). This reduction may explain why they also saw decreases in saquinavir AUC when it was combined with delavirdine and adefovir. In arms where adefovir was not used delavirdine, as expected, increased AUCs of saquinavir, ritonavir and nelfinavir. The reason for this unexpected interaction is not understood because adefovir is not supposed to interact with the p450 system.

New NNRTIs. None of the new NNRTIs discussed here in development have been tested in humans yet. Several new potentially potent NNRTIs from Agouron (AG1549), DuPont (DMP961 and DMP963), and Upjohn & Pharmacia (PNU142721) are in pre-clinical development. All except the MKC-442 show pre-clinical data suggesting they may not be cross-resistant to the currently available NNRTIs. In other words, they might be helpful in salvage therapy for people who have resistance to and failed currently available NNRTIs. Human studies are necessary to explore this potential. The K103N mutation is the main resistance mutation that causes resistance to efavirenz. DuPont researchers suggest from early pre-clinical in vitro experiments that DMP961 and DMP963 show 3 to 8-fold greater potency against viruses containing this mutation. The hope is that these two new NNRTIs will suppress virus resistant to efavirenz, and therefore it might be used in salvage therapy for people who have failed efavirenz. GW420867X is a new NNRTI from Glaxo Wellcome. Early in vitro pre-clinical testing was reported at Retrovirus and its resistance profile suggests it might also be effective for individuals with resistance to current NNRTIs.

Can Virus Levels in Cells Be Monitored to Predict Viral Load Rebound? C. Tremblay, and colleagues, from the Massachusetts General Hospital, reported at Retrovirus that they have developed a simple and sensitive test to measure the amount of virus inside cells. They contend that monitoring cell-associated virus could help predict early failure of therapy in patients with undetectable plasma (blood) viral load. In a pilot study comparing their method to two other methods (ACTG co-culture method and an enhanced culture method using CD8 cell depletion), they reported recovering virus in 11/11 samples; 7 of these 11 were from patients with undetectable plasma viral load (<200 copies/ml). They performed the quantitative version of their test on PBMC (peripheral blood mononuclear cells) from 5 patients who have been undetectable on HAART for an average of 14 months and 4 patients with acute primary infection on triple-drug therapy. Virus was recovered in 8/9 patients. In one patient who had discontinued HAART after 19 months their test predicted plasma viral load rebound.