Treatment Strategies Analyzed at HIV Meeting in Glasgow, Scotland

By Brian Boyle, MD
Unless otherwise indicated all references in the text are to Abstracts of the 7th Congress on Drug Therapy in HIV Infection. November 14-18, 2004. Glasgow, UK.

What to Start ?

Roy M. (“Trip”) Gulick of Weill Medical College of Cornell University, New York, USA started this session with a discussion of “Antiretroviral treatment: what to start?” [PL1.1] Dr. Gulick began by discussing the benefits and risks of antiretroviral (ARV) therapy.

As most clinicians and patients are aware, the benefits of ARV therapy in patients include suppression of HIV RNA levels to undetectable levels, improved CD4+ cell counts, and a decreased risk of HIV-related morbidity and mortality.

There are, however, some hardships and risks associated with ARV therapy and these include the requirement for strict adherence to ARV therapy, which some studies indicating that >95% adherence is required for a high chance of success, the potential short- and long-term toxicities, and the potential for development of drug-resistant viral strains should ARV therapy fail.

In addition, it has been well documented that there is a significant, and possibly growing, risk of ARV drug resistance in untreated HIV-infected individuals and that individuals with baseline ARV resistance have an increased risk for virologic failure on initial treatment regimens. These data support routine baseline resistance testing in some groups of patients, especially those that reside in areas of high ARV-resistance prevalence.

Currently, there are 20 antiretroviral drugs approved for the treatment of HIV infection in 4 classes: (1) nucleoside/tide analogue reverse transcriptase inhibitors (NRTI); (2) non-nucleoside analogue reverse transcriptase inhibitors (NNRTI); (3) protease inhibitors (PI); and (4) entry inhibitors.

Current treatment guidelines recommend starting therapy with 2 nucleoside analogues combined with either an NNRTI or PI(s), and this should be the starting regimen of choice in the vast majority of patients. In some patients, alternatives may be required and alternative initial therapy regimens include: 3 or 4 NRTIs, a 4-drug regimen of 3 NRTIs + an NNRTI, an NRTI-sparing regimen of an NNRTI + PI(s), and a triple-class regimen of NRTI(s) + NNRTI + PI(s).

In order to optimize the patient’s likelihood of long-term success and good health, initial ARV treatment regimens should be simple, convenient, non-toxic, potent, durable, and preserve future treatment options.

A number of recent improvements in ARV therapy have increased the potential for meeting these goals. In recent clinical trials, regimens incorporating newer antiretroviral drugs, including the new NRTI co-formulated once-daily tablets, have provided head-to-head comparisons with previous “standard-of-care” regimens and indicate that the newer, simpler regimens perform as well, and in some cases better, than the older regimens.

In this regard, some initial therapy regimens have demonstrated HIV RNA suppression rates exceeding 70-80% for up to 1-4 years. Dr. Gulick concluded his remarks by stating that “Current options and management strategies for the initial treatment of HIV infection continue to evolve and it is critical to interpret and incorporate newer data into the current standard of care.”

Simplification Strategies

Pietro L. Vernazza of the Infectious Diseases Department of Medicin, Kantons St. Gallen, Switzerland next presented on ”Can antiretroviral treatment be simplified or will triple regimens remain the gold standard?” [PL1.2].

Dr. Vernazza began by stating that since 1996 triple ARV therapy has been considered the gold-standard for the treatment of HIV infection and once the patient starts that therapy he or she tends to stay on it for the rest of his or her life. This therapy carries with it the requirement for high levels of adherence, and, if the patient fails to maintain the required level of adherence virologic failure and the development of drug resistant viruses may occur.

Further, even if excellent drug adherence and virologic suppression can be maintained by the patient, there is always the looming threat of the development of long-term metabolic disturbances or mitochondrial dysfunction. As a result, strategies to limit drug exposure are. Unfortunately, the studies have not been very encouraging.

One proposed strategy, structured treatment interruptions (STIs), held out the potential for increasing HIV-specific immunity and enabling the discontinuation of ARV therapy. In this strategy, the patient discontinues therapy and restarts it when certain CD4 and/or viral load parameters are met. Unfortunately, multiple studies have tried this strategy and failed to demonstrate that it works. While it is still being evaluated, it does not appear that this will be a viable treatment strategy.

Another option for decreasing the risk of toxicity would be to limit the number of drugs or drug classes. Several different strategies have been explored in this regard. It is unclear whether triple nucleoside/tide reverse transcriptase inhibitor (NRTI) regimens are an effective strategy since some triple NRTI regimens have demonstrated limited activity or have only been successful in the maintenance setting.

Protease inhibitor (PI)-only regimens are an attractive strategy in patients suffering from the effects of mitochondrial toxicity of NRTI, but the data for these regimens is extremely preliminary. This strategy involves boosting of PIs with ritonavir which results in plasma trough levels that are far above the inhibitory concentration (IC₅₀) of HIV for many PIs. Several groups have started to evaluate ritonavir-boosted PI monotherapies in different settings.

Dr. Vernazza’s group has published a 48-week pilot study (n=12) using indinavir as the active agent in a maintenance setting (Kahlert et al, AIDS, 2004). Eleven of 12 patients treated with ritonavir-boosted indinavir maintained an HIV-RNA load <50 copies/ml at week 48 but several HIV-RNA blips (<400) occurred.

High rates of indinavir-related nephrotoxicity limit the use of this treatment as a standard trial; however, other groups have studied the use of lopinavir/ritonavir monotherapy either in a maintenance setting (Arribas, Bangkok 2004) or even in drug naive patients (Gathe, Bangkok 2004).

More studies are ongoing in France (lopinavir/ritonavir) and Frankfurt (saquinavir/ritonavir) and the US (atazanavir/ritonavir). Dr. Vernazza’s group has an ongoing trial (ATARITMO) with ritonavir-boosted atazanavir (100/300mg) and all nine patients who were previously treated in the indinavir-mono study have reached the efficacy endpoint of 24 weeks and all patients have maintained their low HIV-RNA load.

Despite this indication of success, Dr. Vernazza has concerns regarding PI-mono therapy including the high frequency of HIV-RNA blips and the poor penetration of some PIs into sanctuary like brain and genital tract. Dr. Vernazza cautions that the long-term effect of this treatment strategy needs to be evaluated in larger studies, before it becomes useful in clinical practice.

Salvage Therapy

Brian G. Gazzard of the  Chelsea and Westminster Hospital, London, UK gave a talk on “Salvage therapy” in his own inimitable, and always entertaining, way. [PL1.3]. Dr. Gazzard noted that the term salvage therapy is an unfortunate one since it raises in his mind images of wrecks on the sea shore. He stated, however, that he would assume that this term means resistance to all three of the presently available classes of drugs.

Dr. Gazzard stated that the scale of multi-drug resistance is presently unclear and he noted that he hopes that resistance to all 4 classes of ARV agents is not that common and that with the correct use of modern antiretroviral therapy this problem may become even less common in the future.

Dr. Gazzard attributed a significant part of the current “salvage” need to patients having received sub-optimal therapy in the past, when limited ARV options existed, or their being poorly adherent to a variety of previous drug regimens.

He noted that in the Chelsea and Westminister Hospital clinic in London, the causes of death among are not primarily related to virological failure and a lack of treatment options, but instead to the development of malignancies or a late presentation that resulted in death before antiretroviral therapy could become effective.

While some strategies have not proven successful in treating salvage patients, various treatment options for salvage patients do exist. The studies regarding the value of a structured treatment interruption prior to starting salvage therapy conflict, with one study from France, that enrolled very advanced patients, suggesting improved outcomes with that approach while another study, which enrolled patients with earlier disease and more treatment options, failed to demonstrate any benefit with that approach and instead showed a detrimental loss of CD+ cells and a risk of clinical progression during the interruption.

Currently, it is not believed that structured treatment interruption in an attempt to cause the virus to revert to wild type is not likely to have a major impact on disease therapy, and may carry significant, additional risk.

There is good evidence, from both from randomized trials and cohorts, that “salvage” patients do better if they stay on some form of ARV therapy; however, efforts are underway to find a “minimalist approach” that would keep the patient on sufficient drugs try and keep the CD4 count as high as possible (the most important predictor of imminent death), while at the same time minimizing pill burden and risk of toxicity.

The fusion inhibitor enfuvirtide (T20), which is now licensed, and the PI tipranavir, which is shortly to enter expanded access and be licensed, have been mainly used in a salvage situation although the optimum positioning of both drugs remains to be determined.

When either of these agents is used as the only active component of a combination, the viral load drops are often short lived although the CD4 count may rise for a more prolonged period. The belief of most clinicians and a post hoc analysis of the major studies performed withT20 (TORO 1 and 2) would suggest that these drugs would be better used in combination with other active agents and, therefore, the best method of treatment in salvage is to prevent it from occurring by using agents more judiciously at an earlier stage of disease.

Dr. Gazzard concluded by mentioning that there are a number of other agents that are being developed in existing drug classes that have novel resistance profiles and are likely to be effective in patients with preexisting resistance. These include new nucleoside reverse transcriptase inhibitors, new NNRTIs Capravirine and TMC125), and new PIs (tipranavir and TMC 114). In addition, novel agents attacking the integrase process, viral entry or viral maturation are also under development.

All of these developments provide hope that even patients in deep salvage can eventually be effectively treated with antiretroviral therapy.

Intermittent Therapy Strategies

Julio Montaner of the B.C.-Centre for Excellence on HIV/AIDS, Vancouver, Canada presented on “Structured treatment interruptions (STI) in the management of HIV-infected individuals.” [PL1.4] Dr. Montaner began by outlining the potential reasons for an STI. These include autoimmunization, reversion to wild-type virus and decreased drug exposure. Dr, Montaner stated that these concepts have now been tested in the settings of primary infection, salvage and chronic infection, with rather disappointing results.

Dr. Montaner first addressed the use of STI in primary HIV infection. While an early study of STI in these patients showed evidence of increased cytotoxic T-cell lymphocytes (CTL), increased HIV-specific CD4+ responses and an ability to control HIV viremia off therapy (Rosenberg ES, et al. Nature. 2000;407:523-526.), continued follow-up of these patients showed evolution of CTL escape mutants, decreasing CD4+ counts and increasing HIV-RNA plasma levels. (Kaufmann D, et al. 11^th CROI; Abst 24.)

Subsequent studies have failed to demonstrate a substantial benefit of STI in this setting. (Markowitz M, et al. J Infect Dis. 2002;186:634-643; Smith DE, et al. AIDS. 2004; 18:709-718. Fidler S, et al. AIDS. 2002;16:2049-2054.) Based on these results STI is not recommended in patients who initiated HAART during primary HIV infection.

Having dismissed the use of STI in patients with primary HIV infection, Dr. Montaner moved on to discuss STI in salvage Patients on a failing HAART regimen with multiple drug-resistance.

These patients may experience a rapid reversion in virus population toward wild type when they stop therapy and this was initially reported to be associated with a better virological response in at least some patients when therapy was re-initiated. (Miller V, et al. AIDS. 2000;14:2857-2867).

It is now clear, however, that the reversion to wild-type virus is associated with an increase in HIV-RNA load and a decrease in CD4+ count. (Deeks SG, et al. N Engl J Med. 2001;344:472-480.)

Three prospective trial have further evaluated this issue. Early positive results from the small short term ANRS 097 study (Katlama C, et al. AIDS. 2004;18:217-226.) failed to be confirmed by the results of Retrogene (Ruiz L, et al. J Infect Dis. 2003;188:977-985.) or CPCRA 064 (Lawrence J, et al. N Engl J Med. 2003;349:837-846.).

The later study actually showed that treatment interruption was associated with not only significant CD4+ cell depletion, but also an increase in clinical events. Based on the demonstrated risk and lack of consistent benefit of STI in salvage, this practice is not currently recommended.

Finally, Dr. Montaner addressed STI in chronic HIV Infection. This strategy was explored in the Swiss-Spanish Intermittent Therapy Trial (SSITT) and failed to show any benefit. (Fagard C, et al. Arch Intern Med. 2003;163:1220-1226.). In addition, failure of STI in chronic HIV infection has also been reported using a 7 days on/7 days off approach. (Ananworanich J, et al. AIDS. 2003;17:F33-37.).

Based on these results STI is not recommended in chronic infection.

While STI does not appear to have a role in treating HIV-infected patients, intermittent therapy has been proposed as one approach to limit drug exposure (for reasons such as adherence, toxicity, cost) and several groups are currently evaluating CD4+ guided therapy interruptions.

Unlike STI, this approach is not expected or intended to provide a direct immunologic or virologic benefit, but instead is intended only as a means to decrease time on ARV therapy and risk of toxicity. To date, this approach appears to be comparable to the continuous therapy arm in several ongoing studies.

However, concerns have emerged regarding premature development of resistance in highly adherent patients following such treatment interruptions.

Consequently, full evaluation of long-term results of such strategy studies will be needed before the possible role of this approach is fully understood. Until then, the only acceptable use of treatment interruptions in clinical practice today pertains to allow recovery from side effects or co-morbidities.

11/17/04