Important note: Information in this article was accurate in September 2004. The state of the art may have changed since the publication date.
 |
The XV International AIDS Conference, held in Bangkok, Thailand in July, was a qualified success. The dire predictions of torrential rains, sweltering heat and humidity, and paralyzing traffic jams with 2-hour commutes to and from the conference center all failed to materialize. Memories of the painfully long flights were quickly erased by the welcoming Thai hospitality and superb cuisine. The city and the conference venue were able to handle the over 17,000 attendees without significant glitches. If the scientific and clinical content was at times underwhelming, attendees acknowledged that this conference is increasingly-and appropriately-becoming the most important forum for the discussion of the global AIDS epidemic and the treatment of HIV infection in the developing world. Of course, the content of the conference might have been richer had investigators from NIH and CDC been allowed to attend and present their data. The government's restriction on travel to this conference was roundly criticized, as were its obsession with abstinence programs and its attempts to foster doubts about the effectiveness of condoms. Activist and community groups from all over the world were well represented in Bangkok, with tactics that ranged from responsible and informed advocacy on the one extreme to the liberal use of whistles, megaphones, fake blood and spray-paint on the other. The international AIDS conferences have always been a colorful mix of science, culture, politics, activism, and theater, and Bangkok was no exception.
The next International AIDS Conference will be held in Toronto in 2006. The 3rd IAS Conference on HIV Pathogenesis and Treatment, which focuses on basic and clinical science, will be held in Rio de Janeiro in 2005.
Clinical Trials of Antiretroviral Therapy
Tenofovir vs Stavudine: Final 3-Year Results
Few new clinical trials were presented in Bangkok, but longer-term data were presented from a number of major studies, including GS 903, the only large 3-year, randomized, double-blind trial of anti-retroviral therapy ever conducted [Gallant JE, et al. Int Conf AIDS. 2004 Jul 11-16;15 (Abstract TuPeB4538)]. In this trial, 600 treatment-naïve patients were randomized to receive either tenofovir DF (TDF) or stavudine (d4T) in combination with lamivudine (3TC) and efavirenz (EFV). The virologic outcomes at the end of the 3-year study were excellent in both arms: 73% and 69% of the TDF and d4T recipients achieved a viral load of <50 c/mL by intent-to-treat (ITT), missing=failure (M=F) analysis, the best results observed in any large randomized trial to date. However, there were important differences in toxicity between the two arms. Patients in the d4T arm had significantly higher fasting triglyceride and LDL cholesterol levels (P<0.01), and the difference in fasting triglycerides continued to increase throughout the 3-year study period. These differences were clinically as well as statistically significant: By the end of the study, 16% of d4T recipients were taking a lipid-lowering agent compared to 5% of those taking TDF (P<0.001). Not surprisingly, peripheral neuropathy was significantly more common in those taking d4T: 31 (10%) of 301 in the d4T group compared to 9 (3%) of 299 patients in the TDF group (P<.001). Similarly investigator-defined lipodystrophy was more frequent with d4T, and occurred in 19% and 3% of d4T and TDF recipients, respectively (P<0.001). The investigators' assessment of lipodystrophy was supported by objective measures as well: Total limb fat as measured by DEXA was higher in TDF-treated patients at both 96 and 144 weeks (P<0.001), and the differences between arms increased during the final year of the study. In addition, patients on TDF had gained an average of 2.9 kg from baseline at 144 weeks compared to 0.6 kg in d4T recipients (P=0.001). No significant renal toxicity was observed in either arm. Patients in both arms experienced a statistically significant decline in bone mineral density at the hip and spine during the first year, which appeared to level off over the second and third years of the study. At 144 weeks, bone loss was greater among TDF recipients in the spine (P=0.001) but not in the hip (P=0.064). The clinical significance of this bone loss is unclear, however, as it ranged from 1.0% to 2.8% loss from baseline. There were actually more fractures in the d4T arm, though all but one were traumatic and not felt to be due to osteopenia.NNRTI resistance mutations and M184V were the most common mutations observed among patients failing therapy in both arms. Among those who failed therapy on the TDF arm, 7 developed K65R in the first year of therapy and 1 in the second year. No patient developed K65R in the third and final year of the trial. Thus K65R was present in approximately 17% of the TDF recipients who failed therapy and in less than 3% of the total number of patients treated with TDF.
In a sub-analysis of the women participating in GS903, DeRuiter found that the virologic response was similar between men and women, though women had a greater increase in CD4 count [Abstract MoOrB1083]. Men taking d4T were much more likely to have significant increases in fasting triglycerides than women. Women experienced greater losses in bone density than men, though there were no fractures among women.
These results, also published during the same week [JAMA. 2004 Jul 14;292(2):191-201], are important because they demonstrate the potency and durability of two simple regimens, one of which (TDF/3TC/EFV) is now available as a once-daily regimen. They also show clear differences in toxicity between the two arms, without a significant cost in terms of drug resistance. The results have been extrapolated, by clinicians, the FDA, and the IAS-USA Guidelines Panel, to the combination of TDF + emtricitabine (FTC) + EFV, and the fixed-dose coformulation of TDF/FTC (Truvada) was recently approved by the FDA.
CLASS: 96-Week Data
John A. Bartlett from Duke presented 96-week data from the CLASS study, a comparison of EFV, ritonavir-boosted amprenavir (APV/r), and d4T, each combined with a nucleoside backbone of abacavir (ABC) + 3TC [Abstract TuPeB4544]. In contrast to earlier presentations of the data, where the EFV regimen was associated with better virologic responses (proportion with VL <400 c/mL by ITT analysis) than the d4T or APV/r regimens, the 96-week data showed no difference in virologic suppression to <400 c/mL by ITT, M=F analysis. However, the d4T arm was inferior by on-treatment analysis, and also by ITT M=F analysis in patients with baseline viral loads >100,000 c/mL. Duration of suppression was significantly longer in the EFV arm than in the d4T arm (P=0.007). Of the three CLASS regimens, only the EFV-based combination is still widely used today. This study, along with a number of others using a variety of regimens, supports the use of the ABC/3TC nucleoside backbone, which is now available as an FDA-approved fixed-dose coformulation (Epzicom).Efavirenz vs Indinavir: 3-Year Data from the 006 Trial
Karen Tashima presented the final 3-year data from DuPont 006, an early study that compared EFV and indinavir (IDV), both given in combination with zidovudine (AZT) and 3TC [Abstract TuPeB4547]. CD4 counts continued to rise throughout the treatment period, and after 3-years of therapy, approximately half of the EFV-treated patients had viral loads <400 c/mL, which was significantly better than the results for the IDV-treated patients. While this is a lower rate of suppression than was seen in the GS 903 study, approximately 15% of those in the 006 trial had received prior nucleoside analog therapy, whereas those in the GS 903 trial were all treatment-naïve.Fosamprenavir Studies in Treatment-Naïve Patients
Edwin de Jesus presented 48-week data from the SOLO trial, a comparison of once-daily ritonavir-boosted fosamprenavir (FPV/r) vs twice-daily nelfinavir (NFV), both combined with an ABC/3TC backbone given twice daily in treatment-naïve patients [Abstract TuPeB4503]. While the overall results were comparable, post-hoc analyses demonstrated that patients with high viral loads and low CD4 counts appeared to have better responses to FPV/r than to NFV, and the 48-week virological response to FPV/r (suppression to <400 c/mL) was not affected by baseline viral load or CD4 count, in contrast to the NFV arm. It is unclear whether these differences are statistically significant, however, because the study was not powered to demonstrate differences in these post-hoc analyses. Patients who developed virologic failure in the FPV/r arm had no evidence of protease inhibitor (PI) resistance and less nucleoside analog reverse transcriptase inhibitor (NRTI) resistance than those who failed in the NFV group. The differences in resistance appeared to be more pronounced among those with low CD4 counts and high viral loads at baseline. These results are consistent with those from several lopinavir/ritonavir (LPV/r) trials in PI-naïve patients. To date no PI resistance has been observed in patients failing LPV/r in these trials, including the 720 study, in which no PI or thymidine analog resistance has been observed after 5-years [Hicks C, et al. Abstract WeOrB1291], and the 863 trial, which demonstrated no PI resistance and significantly less NRTI resistance in the LPV/r arm compared to the NFV arm [Walmsley SL, et al. N Engl J Med. 2002 Jun 27;346(26):2039-46]. It now appears that PI resistance can occur in PI-naïve patients failing therapy, but the fact that these cases are rare enough to be publishable is remarkable.While FPV/r was administered once a day in this trial involving treatment-naïve patients, it should be noted that in treatment-experienced patients enrolled in the CONTEXT trial, efficacy of once-daily FPV/r (1400/200 mg qd) was inferior to that of twice-daily FPV/r (700/100 mg bid) [Elston, et al. Abstract MoOrB1055]. Unboosted FPV was superior to NFV in treatment naïve patients in the NEAT trial [Brutus A, et al. Abstract TuPeB4500], in puzzling contrast to the overall results of the SOLO trial, in which unboosted FPV and NFV were comparable. Nevertheless, boosted FPV is likely to be preferred over unboosted FPV, given the better resistance profiles among patients who fail therapy and the high cost of unboosted FPV.
Enfuvirtide: 96-Week Results from the TORO Trials
Arasteh presented 96-week results from the TORO studies, the pivotal multinational trials in treatment-experienced patients that led to the approval of enfuvirtide (ENF, T-20) [Abstract MoOrB1058]. These long-term results demonstrated durability of response in patients randomized to take ENF along with an optimized background (OB) regimen. Since patients in the control (OB alone) arm crossed over and added ENF at 48 weeks, the data at 96 weeks are not controlled. Over half of those randomized to the ENF + OB arm remained on therapy at 96 weeks, which is impressive given the fact that this was a highly treatment-experienced group. The 96-week data demonstrate that the majority of patients whose viral loads were suppressed at week 48 maintained suppression at week 96, using both the 400 c/mL and the 50 c/mL threshold, and CD4 counts remained fairly stable. These data support the durability of response to ENF in patients who have a short-term response to therapy, and emphasize the importance of using this drug in combination with other active drugs whenever possible.
Monotherapy for Virologic Suppression
Several studies looked at the once radical idea of monotherapy with LPV/r in treatment-naïve patients. Gathe reported 48-week results from the IMANI-1 study, in which 30 patients initiated treatment with LPV/r alone [Abstract MoOrB1057]. A higher dose of LPV/r (533/133 mg bid) was used in those who weighed more than 70 kg. Ten of the 30 discontinued therapy, mostly for reasons unrelated to treatment. Of the 20 who remained on therapy, all had a viral load <400 c/mL at 48 weeks (90% <50 c/mL). Thus, by ITT, non-completer=failure (NC=F) analysis, suppression to <400 c/mL and <50 c/mL was achieved in 67% and 60%, respectively. Mean CD4 count increase was 317 cells/mm3 at 48 weeks.
Arribas presented the results of the Only Kaletra (OK) study, a 24-week randomized, open-label, multicenter study from Spain in which 42 patients who were on an LPV/r-based regimen for at least one month with CD4 counts >800 cells/mm3 and viral loads <50 c/mL for at least 6 months, were randomized to remain on LPV/r + 2 NRTIs or to switch to LPV/r monotherapy [Abstract TuPeB4486]. All patients who remained on combination therapy maintained a viral load <50 c/mL at week 24. In contrast, there were three participants (14%) who experinced virologic failure among the 21 randomized to LPV/r monotherapy, with the remainder of the patients maintaining virologic suppression. Interestingly, lopinavir trough concentrations were adequate in 2 of the 3, and none of the patients had demonstrable PI resistance. Virologic suppression was achieved with reintroduction of the original NRTIs. Similarly, in a report of 19 patients treated with LPV/r monotherapy following virologic suppression on HAART, there was one case of unexplained virologic failure [Ruane P, et al. Abstract TuPeB4577], and in Gathe's IMANI study, one patient failed to achieve complete virologic suppression on LPV/r monotherapy despite excellent LPV levels and no evidence of PI resistance. His virus became suppressed when his regimen was intensified with tenofovir and lamivudine. There was also one unexplained virologic failure in a study of 18 patients who switched from a stable NNRTI-containing regimen to LPV/ monotherapy [Pierone G, et al. Abstract TuPeB4595]. The reasons for these anecdotal unexplained failures with LPV/r monotherapy remain unclear. One hypothesis is that there may be anatomic or pharamacologic "compartments" that PIs can't penetrate. If this were the case, it would be a major obstacle to the idea of monotherapy, at least with PIs. Nevertheless, none of these failing patients appears to have developed resistance as a result of monotherapy failure, and larger trials of this still investigational strategy are ongoing.
Monotherapy to Prolong Treatment Interruption
The M184V mutation, which emerges in patients failing 3TC- or FTC-containing regimens, is known to decrease viral replicative capacity (RC), potentially slowing clinical and immunologic progression. For this reason, the usual dictum is that 3TC or FTC should be maintained in patients taking a non-suppressive regimen, though this concept has not been carefully studied. Castagna presented data from a small but intriguing study in which patients known to have an M184V mutation who were intending to interrupt therapy with a failing regimen (viral load >1000 c/mL) were randomized either to stop therapy completely or to continue 3TC alone [Abstract WeOrB1286]. Preliminary 24-week data demonstrated a number of distinct advantages to continuing 3TC, including a significantly slower decline in CD4 count and a lower viral load rebound after discontinuing HAART. The proposed mechanism was supported by the fact that replication capacity remained low in those who remained on 3TC but increased substantially in those who stopped all therapy. Moreover, not only was the M184V mutation maintained in the monotherapy group, but other reverse transcriptase mutations persisted as well, suggesting linkages of mutations on the same virions. Therefore, the magnitude of benefit might not have been the same had 3TC been restarted following a period of time off therapy, since it would have selected only 3TC-resistant mutants without other mutations.
Of course, the other advantage of this approach is that it has no clear downside: No new mutations emerged as a result of 3TC monotherapy, nor would any be expected. M184V causes such high-level resistance to 3TC that there is little reason for the virus to develop additional mutations despite continued therapy. However, an important caveat, aside from the small sample size and the preliminary nature of the results, is that these were not "salvage" patients: They all had CD4 counts above 500 cells/mm3 and were stopping for a variety of reasons that did not necessarily have anything to do with treatment failure. Despite the benefits of 3TC monotherapy, their CD4 counts still declined. Such a strategy might not be appropriate for patients at more advanced stages of disease, for whom more aggressive salvage regimens might be required, even if they weren't fully suppressive. Instead, it might best be viewed as a way to delay the need for resumption of HAART in patients who are stopping therapy with high CD4 counts. At the present time it should be considered only in those who have already developed the M184V mutation, though this study raises the intriguing question of whether there might be a benefit to this approach even in treatment-naïve individuals. Would a long delay in the need for HAART ever justify sacrificing 3TC and FTC as active antiretroviral agents?
Treatment Interruption Studies
…and speaking of treatment interr-uption, there were a number of presentations on intermittent therapy, especially those involving so-called "CD4-guided approaches," in which patients doing well on HAART stop therapy; restarting based on a predetermined fall in CD4 count. In the HIV-NAT 001.4 trial, a small pilot study conducted in Thailand, patients on stable antiretroviral therapy with CD4 counts above 350 cells/mm3 were randomized either to continue HAART, to switch to a one-week-on, one-week-off schedule, or to stop therapy until the CD4 count fell below 350 cells/mm3 [Ananworanich J, et al. Abstract WeOrB1283]. The one-week-on, one-week-off arm was terminated early because of a high rate of virologic failure. However, at the end of the 96-week study period, there was no significant difference in virologic failure (viral load >500 c/mL) between the continuous therapy arms or the CD4-guided arm. While CD4 counts were higher among those randomized to receive continuous therapy, there was no difference in the proportion of patients who maintained CD4 counts above 350 cells/mm3. And in contrast to patients on continuous therapy, those in the CD4-guided arm spent only 46% of the study period on HAART. While this was not associated with measurable differences
in quality of life, it clearly has important cost implications, which are especially relevant in developing countries.
This strategy was supported by a number of other studies presented in Bangkok, most of which found that therapy could be safely interrupted in some patients doing well on HAART, but confirmed findings from prior observational studies regarding predictors of successful interruption [Ruiz L, et al. Abstract TuPeB4567; Mussini C, et al. Abstract TuPeB4569; Katzentstein DA, et al. Abstract TuPeB4585]. Specifically, patients with relatively higher CD4 nadirs were able to remain off therapy longer than those who began HAART with lower CD4 counts. Other predictors included lower pre-HAART viral load and longer duration of virologic suppression on HAART. These findings raise questions about our current guidelines for initiation of therapy in naïve patients. By waiting until the CD4 count is between 200 and 350 cells/mm3, are we essentially committing our patients to continuous therapy for life? Perhaps earlier initiation of therapy in naïve patients would allow many to take therapy intermittently, resulting in less cumulative time on HAART and less long-term toxicity.
On the other hand, there are a number of potential drawbacks to intermittent therapy. Viral rebound increases the risk of transmission. Discontinuation of therapy may place patients at risk for drug resistance, especially with regimens containing NNRTIs, which have long half-lives and are vulnerable to high-level resistance with single point mutations. And while short-term data from cohort studies show no clear disadvantage to remaining untreated with a CD4 count above 350 cells/mm3, that could change with longer-term data. For example, while the risk of opportunistic infections is minimal above that threshold, there may be an increased long-term risk of lymphoma or neurologic complications. Data from the GS 903 trial, among others, suggest that bone mineral density decreases with initiation of antiretroviral therapy. If that's true for all regimens, what are the long-term consequences of repeated starts and stops? Allowing the CD4 cell count to decline before starting or resuming therapy may increase the likelihood of a shift from an CCR5-tropic virus to a CXCR4-tropic virus or a mixed X4/R5 phenotype [Harrigan PR, et al. Abstract MoPeB3117], which will become increasingly relevant with the development of new CCR5 antagonists [See also, Shepherd J and Quinn T, HHR 2004;16(4):1]. Finally, as antiretroviral therapy gets safer and easier, the risk:benefit ratio may shift in favor of earlier continuous antiretroviral therapy, despite the apparent short-term safety of CD4-guided treatment inter-ruption strategies.
Induction-Maintenance Strategies
Marty Markowitz from the Aaron Diamond Research Center presented data from a large trial in which 448 patients were started on a regimen of AZT/3TC/ABC + EFV [Abstract LbOrB14]. Those who had viral loads below 50 c/mL at 1 year were randomized to continue 4-drug therapy or to discontinue EFV and remain on the triple-NRTI combination for another 48 weeks. Unfortunately, interpretation of the results of this study is complicated by the fact that almost 40% of the participants dropped out of the study during the first year of therapy prior to randomization. Nevertheless, the results demonstrated that overall efficacy of the simplified maintenance regimen was non-inferior to the 4-drug combination by an intent-to-treat analysis. On the other hand, virologic failure was more common in the triple-NRTI arm (11% vs 6%), which was balanced out in the ITT analysis by a higher drop-out rate in the EFV-containing arm. Patients failing therapy on the EFV-containing arm tended to have 3TC and EFV resistance (M184V and K103N), while those failing triple-nucleoside therapy typically had M184V and thymidine analog mutations. The high drop-out rate and the higher rate of virologic failure in this study make it hard to use these results to guide clinical practice. Nevertheless, it seems clear that response to triple-NRTI therapy may be better in patients whose viral load is already suppressed on a standard HAART regimen than in those who start therapy with a triple-NRTI regimen. For now, the question of whether we can safely "deintensify" therapy after achieving virologic suppression remains open.
It is worth noting that a meta-analysis of studies comparing 4- vs 3-drug regimens for initial therapy showed no advantage of a fourth drug [Moyle GK, et al. Abstract TuPeB4519]. We are all eagerly awaiting the final results of ACTG 5095, which will compare AZT/3TC + EFV and AZT/3TC/ABC + EFV. Will the addition of a third NRTI further improve the efficacy of an already highly effective regimen?
The high rate of virologic non-response associated with the triple-NRTI regimen of ABC, 3TC, and TDF has been documented in three clinical trials and has been discussed in previous issues of The Hopkins HIV Report. Recent data suggest that the failure of this regimen was not due to an intracellular interaction or antagonism between ABC and TDF [Hawkins T, et al. Abstract TuPeB4627; Miller JD, et al. Abstract WeOrB1237]. The favored hypothesis of the day is the low genetic barrier to resistance: both ABC and TDF exert selective pressure on K65R, which decreases susceptibility to all three drugs in the regimen. In a poster presentation, results from studies examining a variety of ABC/3TC-containing regimens were analyzed, including the triple-NRTI combination of ABC/3TC/AZT [Gallant JE, et al. Abstract TuPeB4502]. Non-response ranged from 0% to 24% across the trials, in sharp contrast to the 74% observed in ESS 30009, the largest of the ABC/3TC + TDF trials, pointing out that not all triple-NRTI regimens are the same and supporting the viability of the ABC/3TC backbone in other combinations.
Egger presented the results of a meta-analysis of 13 different studies from 12 cohorts comprising the large Antiretroviral Therapy Cohort Collaboration (ART-CC), representing over 60,000 person-years of follow-up [Abstract TuOrC1157]. The analysis looked at changes in survival between 1995 and 2003. Mortality rates declined between 1995 and 1998 as a result of HAART, but did not decrease further between 1998 and 2003. In fact, in some cohorts, primarily those with a large proportion of injection drug users, mortality and development of new AIDS diagnoses increased during that time period, whereas there was a further decrease in these outcomes among men who have sex with men.
Data from the EuroSIDA cohort assessed the durability of virologic suppression among patients who achieved an undetectable viral load on their initial HAART regimen [Phillips A, et al. Abstract TuPeB4542]. Patients treated with nelfinavir-based regimens were more likely to experience virologic rebound than those treated with efavirenz. While this was also true of nevirapine- and abacavir-based triple-NRTI regimens in patients with prior pre-HAART nucleoside analog therapy, it was somewhat surprising that treatment-naïve patients treated with triple-NRTI regimens were no more likely to rebound than those treated with efavirenz, in contrast to other studies, including ACTG 5095.
A retrospective case-control study using mortality data from San Francisco found that patients initially treated with the four "3x5 regimens" recommended by the WHO for use in developing countries (AZT/3TC or d4T/3TC plus either EFV or NVP) had the best survival compared to those treated with other regimens (mostly unboosted PI-based combinations) [Chen SY, et al. Abstract MoOrC1082]. This study offers support for the choice of regimens by the WHO. However, the ability to generalize these findings is limited by the lack of follow-up regimens in many developing countries. In addition, the study design is subject to selection bias: NNRTI-based regimens may have been more widely used by more experienced clinicians or may have been prescribed to patients more likely to adhere to therapy.
Complications of HIV Infection and Antiretroviral Therapy
A few brief bullets on complications associated with HIV infection and its treatment:
Those of us attending the "Track B" clinical sessions couldn't help but feel that we were on the sidelines, missing out on the real "action" of the conference. That is, the politics, the epidemiology, and the discussions of treatment delivery in the developing world: what's working, what's not, and what remains to be done. Since the groundbreaking XIII conference in Durban in 2000, where treatment of HIV infection in resource limited countries was taken seriously for the first time, we have made some progress, but we have a long, long way to go before we come close to realizing the goal expressed in the theme of the Bangkok conference: "Access for All."
20040901
JH20040901
©1997-2004. 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 Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.
AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2004. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1980, 2004. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.
