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Not All Triple Nucleoside Therapies are the Same
  Written by: Maggie Hemedah and Brett Moskowitz
Treatment of HIV with triple nucleoside therapy has become somewhat controversial. While the effectiveness of newly tested triple nucleoside strategies for initial therapy with tenofovir (Viread®; TDF) + didanosine (Videx®; ddI) + lamivudine (Epivir®; 3TC) and with TDF + abacavir (Ziagen®; ABC) + 3TC has been shown to be quite poor, previously tested combinations of 3 nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine [Retrovir®; ZDV] or stavudine [Zerit®;d4T] with 3TC and ABC) remain in the current Department of Health and Human Services (DHHS) guidelines as alternatives for initial therapy in those who choose not to use boosted protease inhibitors (PIs) or nonnucleoside RTIs (NNRTIs).
This article examines the characteristics of the different triple nucleoside combinations and outlines the potential benefits and shortcomings of these regimens. It also provides perspective on these issues from John A. Bartlett, MD, Professor of Medicine, and Clinical Research Director at the Duke Center for AIDS Research, Duke University Medical Center, Durham, North Carolina.
The first phase III randomized, double-blind study (CNA 3005) comparing the activity of triple nucleoside therapy with a PI-based therapy examined the efficacy of 3TC/ZDV (Combivir®) with ABC versus 3TC/ZDV with the PI indinavir (Crixivan®; IDV). In the study, 562 treatment-naive patients received 16 pills daily as part of the regimen. At 48 weeks, the triple NRTI regimen was equivalent to the PI-based regimen as measured by the proportion of patients achieving HIV RNA £400 copies/mL (c/mL) (51% in both groups; intent-to-treat [ITT] analysis). The regimens appeared comparable as measured by the proportion of patients with HIV RNA <= 50 c/mL: 40% in the ABC group versus 46% in the IDV group. However, in patients with baseline HIV RNA >100,000 c/mL, the proportion of patients with HIV RNA £50 c/mL was greater in the IDV arm (45%) than in the ABC arm (31%).
These results led to a subsequent study, CNA 3014, which compared the same regimens (ABC with 3TC/ZDV [n=169] versus IDV with 3TC/ZDV [n=173]) in an open-label study with the administration of fewer pills. Results showed that the triple NRTI regimen was comparable to the PI regimen regardless of baseline viral loads; however, the proportion of patients whose virus was suppressed on ABC therapy was higher in those with baseline viral loads <100,000 c/mL than in those with higher baseline viral loads—a difference that was not seen in the IDV study subjects.
At 48 weeks, the proportion of patients with HIV RNA <400 c/mL was 64% in the ABC group compared with 50% in the IDV group (ITT analysis; switch/M=F). The proportion of patients with HIV RNA <50 c/mL was 59% in the ABC group versus 48% in the IDV group.
Recently, a large randomized, double-blind study (AIDS Clinical Trials Group [ACTG] 5095) compared a coformulation of the same triple nucleoside combination ABC/3TC/ZDV (now known as Trizivir®) with 2 NNRTI-based regimens, 3TC/ZDV+efavirenz (Sustiva®; EFV) and ABC/3TC/ZDV+EFV. Results showed that ABC/3TC/ZDV was not as potent as the pooled EFV-based regimens, forcing the ACTG to halt the triple nucleoside arm. The proportion of patients with HIV RNA <200 c/mL at 48 weeks was 89% in the pooled EFV arms compared with 74% in the Trizivir arm (ITT analysis). The difference in response rates between the EFV-containing arms and the Trizivir arm was seen in patients with viral loads above and below 100,000 copies/mL at the start of treatment. It should be noted that the Trizivir arm of ACTG 5095 did not perform poorly compared with previous studies evaluating this regimen (74% success), but the EFV-containing regimens performed extremely well (89% success). In addition, the pill count rose from 2 pills per day to 7 pills per day for those on Trizivir, thereby lessening the potential for an adherence benefit.
In the CLASS study, a dual-NRTI backbone of ABC and 3TC BID was used in combination with an NNRTI, EFV; a ritonavir (Norvir®; RTV)-boosted PI, amprenavir (Agenerase®)/ritonavir (APV/r); or a third NRTI, d4T. At 48 weeks, the triple NRTI combination ABC, 3TC, and d4T showed efficacy comparable to the RTV-boosted PI regimen (HIV RNA <50 c/mL in 73% of patients in both groups; ITT-observed analysis), but not to the EFV-containing regimen (HIV RNA <50 c/mL in 93% of patients). In the ITT missing=failure analysis, 76%, 62%, and 59% in the EFV, d4T, and APV/r arms, respectively, had HIV RNA <50 copies/mL at week 48. Again, this suggests that NNRTI-based regimens may have greater effectiveness.
Despite the apparent greater effectiveness of NNRTI-based regimens, there are instances in which triple nucleoside regimens may still be preferred. According to Dr Bartlett, an HIV specialist at Duke University Medical Center, "the greatest potential benefit of triple nucleoside combinations is simplicity. By and large," he says, "the small number of pills promotes better adherence." He adds that while a preferred regimen for the treatment of HIV-infected patients includes an EFV-containing combination or a lopinavir/r (Kaletra®; LPV/RTV) - containing combination, he would consider prescribing fixed-dose combination ABC/3TC/ZDV to a patient who has a relatively low baseline HIV RNA <100,000 c/mL and in whom adherence is an issue. In fact, Dr Bartlett recounts several incidences in which patients have asked to take Trizivir and nothing else "because they only want to take 1 pill twice per day."
When asked if there are other effective uses for triple nucleoside therapies, Dr Bartlett cites triple nucleoside therapy as a means of simplifying treatment in patients on PI-containing combinations. "In this context," he says, "it has been shown to be effective in maintaining suppression of HIV RNA as long as the patient did not have a prior nucleoside experience. Potential benefits of using this approach include improvement in lipid abnormalities and improvements in glucose intolerance," he adds.
In response to whether patients are shying away from triple nucleosides and seeking more potent therapies, Dr Bartlett explains that after the ACTG 5095 study, he offered his patients intensification with nevirapine (Viramune®; NVP), EFV, or TDF, but that every patient declined. "They are choosing the ABC/3TC/ZDV combination because it is a known quantity, and they do not wish to risk adding an unfamiliar drug," he says, "not just in terms of convenience, but with regard to toxicity. Every drug has some potential side effect," he adds, citing EFV, which is associated with sleep and other neurological disorders, and PIs, which are linked to diarrhea and lipid abnormalities. "There's a perception that PIs and nonnucleosides have greater side effects and toxicities and some people don't want to take a chance. That is not to say that nucleosides are totally benign," he says, "but you have to weigh it out in the care of the individual patient. Part of it is that people are more aware of the risks of PIs, such as lipodystrophy, than the mitochondrial toxicity of nucleosides. Neurologic disorders found with EFV may be better known than the side effects of NRTIs, such as mitochondrial toxicity. Some patients come in and say they don't want d4T+ddI owing to the potential lipodystrophy, especially lipoatrophy—they are not aware of the other possible effects of mitochondrial toxicity with d4T+ddI, such as pancreatitis."
Other triple nucleoside combinations have not fared as well as ABC/3TC/ZDV or d4T+3TC+ABC. The combination TDF+ABC/3TC was recently associated with high treatment failure rates and selection of the M184V/I mutation with or without the K65R mutation. A smaller open-label, single-center study of the once-daily combination of TDF+3TC+ddI was terminated after 20 of 21 patients experienced virologic failure at 12 weeks with selection of the M184V/I mutant with or without K65R.
M184V/I or wild-type virus are the most common mutations in the setting of virologic failure on ABC/3TC/ZDV. Over months, there may be the additional selection of thymidine analog mutations (TAMs) that confer cross-resistance to all NRTIs. According to Dr Bartlett, "the issue of resistance is important if patients are allowed to stay on a triple nucleoside regimen with a detectable viral load for more than 6 months. In the presence of viremia," he says, "they will accumulate additional mutations in the RT gene. Ultimately, these mutations may result in a compromised response to NRTIs in the future." Dr Bartlett cites the CNA 3005 96-week substudy of patients experiencing virologic failure who were on ABC/3TC/ZDV. In that study, the M184V mutation or wild-type virus were the most common genotypes, even after continuing the failing regimen for several months. After a median of more than 6 months of maintaining the wild-type virus or the M184V mutation alone in the face of viral replication, patients tended to accumulate TAMs. According to Dr Bartlett, "the danger of this lies in compromising the response to other nucleoside and nucleotide RTIs in the future. In the ACTG 5095 study—which used a more stringent definition of virologic failure—the resistance pattern on the triple nucleoside regimen was simple, and more commonly included just the M184V mutation or wild-type virus. Data didn't go beyond 6 months. Data from the 2 studies are consistent," Dr Bartlett says. "Early on, the wild-type virus or M184V mutation are present in those experiencing virologic failure. If patients stay on the failing triple nucleoside regimen, over time, TAMs may accumulate—a factor that has important implications for future options."
The conundrum of whether patients taking Trizivir should have their viral loads closely monitored or whether patients with the M184V mutation experiencing failure at 6 months should change their regimen, "is very complicated," Dr Bartlett says. "Attenuated viral fitness is associated with nucleoside analog resistance mutations, and therefore people may have a low level of viremia and may be accumulating these resistance mutations. Yet their viremia may be at such a low level that it is not possible to perform a genotypic resistance test," he says, adding that the question remains unanswered. More information is expected this summer from the CLASS study (to be presented at the World AIDS Conference). Regarding regimen changes, Dr Bartlett claims that it would be difficult to tell whether it is better to switch regimens or stay on the triple nucleoside regimen. "It may still be convenient to have an easy 2-tablet regimen that keeps viral load manageable," he says, "but mutations may still continue to evolve. It's difficult to tell over the long term whether it is better to switch or stay with the regimen that is still suppressing HIV RNA very effectively—but just not below the limit of detection. Though there is nothing to suggest there is a right choice," he says, "the benefit of staying on a triple nucleoside regimen is that only a limited number of HIV drug combinations can be used, and if you are able to gain more time on any given regimen, this will ultimately help patients survive longer without disease progression. It may also potentially avoid toxicities of future regimens." The challenge in each of these considerations may influence the decision, and we don't really have an appreciation of what the balance is," Dr Bartlett says. "There are opinions, but not a whole lot of evidence to suggest an absolute right choice. People may be polarized in the opinions they express, but we need evidence-based data to guide patients and their providers to reach the right decision."
If it is not possible to use an NNRTI- or PI-based regimen in initial therapy, 2 triple NRTI regimens may be considered: ABC/3TC/ZDV (available as Trizivir in a fixed-dose combination) or d4T+3TC+ABC. Although it may also be possible to use emtricitabine (Emtriva®; FTC) in place of 3TC, this has not been studied. The other 3 NRTI regimens that have recently been tested, TDF + 3TC with either ddI or ABC, have not been successful and should not be used.
ZDV or d4T with ABC and 3TC may be used as initial therapy or as simplification. As initial therapy, they may allow the preservation of future treatment options because they select for M184V first and do not accumulate TAMs for months after initial virologic failure. However, after 6 months on these regimens additional nucleoside drug mutations may accumulate and we are not yet certain as to the risks related to that. These regimens rarely select for K65R, and ZDV may actually prevent the selection of K65R. ABC/3TC/ZDV and d4T+ABC+3TC may also prove useful in simplification strategies for patients with advanced disease taking problematic PI-based regimens and quadruple therapy.
We have seen from important studies in the past year that certain triple nucleoside regimens (ABC/3TC+TDF and ddI+3TC+TDF) have resulted in high viral failure rates and should be avoided. On the other hand, Trizivir (ABC/3TC/ZDV) has a track record of success in treatment and does not result in these high viral failure rates. Study results of Trizivir discussed above show that in patients with viral loads >100,000 c/mL, Trizivir is not as effective as in patients with <100,000 c/mL; PI- and NNRTI-based regimens are likely to be more potent.
Effectiveness is slightly different from potency. A regimen can be more potent, and PI and NNRTI regimens are more potent, but a regimen is only effective if you take it. Potency and effectiveness of a regimen are linked to adherence.
All NRTIs have been linked as a potential cause of lipoatrophy. However, studies show that d4T is most closely linked to the development of lipoatrophy. For this reason, some patients choose to delay the use of d4T. There may be certain circumstances under which the use of d4T is less likely to lead to lipoatrophy, such as when CD4 counts are high, but this has not been established. Preliminary study results suggest that TDF may be less likely to lead to lipoatrophy than other NRTIs.
Supported by an independent grant from GlaxoSmithKline
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