Therapeutic and diagnostic advances in the HAART era.

It has been almost 10 years since the approval of the first protease inhibitor, saquinavir (Invirase) in December 1995. Since that time, there have been great advances in treatment monitoring, treatment strategies, and overall knowledge about the pathogenesis of the disease, but we are still far from a cure and the virus continues to outsmart all the advances that have been made.

Results from the first-generation protease inhibitor--saquinavir, ritonavir (Norvir), and indinavir (Crixivan)--combination studies were greeted with much excitement as they showed a profound effect on survival and ability to control virus replication. Starting in 1996, several studies and cohorts demonstrated dramatic decreases in mortality and opportunistic infections with the widespread availability of the protease inhibitors. The term "HAART" (highly active antiretroviral therapy) was first used around this time.

The use of viral load testing in studies investigating the protease inhibitors was another cause for excitement. These tests, using polymerase chain reaction (PCR) or branched DNA (bDNA) technology, offered a more direct method of measuring the treatment effect on the virus in blood, as well as other tissue compartments, compared to measuring p24 antigen or CD4 cells. For the first time, it was possible to measure how quickly viral load (HIV levels) dropped with the initiation or switch of therapy and to determine when a treatment regimen was starting to lose effectiveness as indicated by a rebound in viral load. The availability of the protease inhibitors and viral load testing resulted in a paradigm shift in how people with HIV were treated.

The initial protease inhibitor studies clearly showed that people had to be very adherent when taking these medications. There was a massive effort by community-based organizations, as well as the research establishment and the pharmaceutical companies, to promote adherence.

The results from studies with protease inhibitors were met with so much enthusiasm that many researchers were discussing the possibility of eradicating the virus from a person's body. Different strategies were explored from using 4 or more drugs for people who recently became infected to using drugs to "flush out" the reservoirs and then using HAART. However, none of these strategies were successful and the work by Bob Siliciano examining the half-life of the virus in latently infected cells further demonstrated how difficult it would be to eradicate the virus.

With the introduction of 3 protease inhibitors within a few months of each other, there was tremendous marketing pressure from the 3 companies that manufactured these products, leading to intense debates among the companies involved. One area of concern dealt with the potential resistance and cross-resistance to these drugs. It was not until the results from ACTG 333 were announced, showing that there was indeed cross-resistance between these drugs, that the issue was resolved. This experience taught the community to be very skeptical about how data were presented. Another lesson learned was that the less drug resistance is studied and the earlier the drug is in put into clinical development, the better the drug looks. It has become an unfortunate reality for most of the drugs that many "problems" are discovered only after it has been more extensively studied or been on the market for a few years.

The early excitement generated with the protease inhibitors soon turned to more guarded optimism. Many people did not achieve durable virologic benefits from these drugs, mainly because they had previously taken and developed resistance to the nucleoside analog reverse transcriptase inhibitors (NRTIs). As a result, they were virtually being treated with protease-inhibitor monotherapy. It also became evident that these drugs came with their own set of side effects. Ritonavir caused nausea and diarrhea, and indinavir caused kidney stones. Saquinavir did not cause many side effects, mainly because the drug was poorly absorbed and in comparison to the other 2 protease inhibitors, did not produce as large a viral load reduction. It soon became clear that to get maximal virologic benefit from the protease inhibitors, they had to be combined with 2 drugs, or at a minimum one new drug that the individual had not previously taken, and that these new drugs could not be cross-resistant with any of the drugs that were previously used.

Several strategies were explored for people who had few or no treatment options. Many groups reported some virologic success with a megaHAART or multidrug rescue therapy (combining 4 or more drugs). However, these regimens were generally not well tolerated and drug interactions made these regimens difficult to manage. Another strategy with reported early success was Structured Treatment Interruptions (STIs). The goal was for individuals to stop their antiretroviral therapies to allow drug-resistant HIV to revert back to wild-type virus and then start a megaHAART regimen. Small short-term studies showed a good virologic response. However, larger studies indicated that this strategy was actually potentially harmful, as people taking an STI were more likely to experience an opportunistic infection and disease progression compared to those continuing on a HAART regimen.

Another problem with many of the early protease inhibitors was the complicated dosing schedule. Many of these drugs had to be taken 3 times a day, making adherence especially challenging for many people. The middle dose was particularly difficult for people who had jobs and especially since many of these drugs also had food requirements. One strategy to achieve twice-daily dosing with the protease inhibitors was to exploit the inhibitory effects of ritonavir on the cytochrome p450 3A4 enzymes. Ritonavir has a potent effect on the cytochrome p450 3A4 enzymes in the liver such that when it is combined with another protease inhibitor (or any drug that is metabolized or affected by this enzyme), drug levels of the other drug are dramatically increased and the resultant lowered metabolism causes the other drug to stay in the body for a longer period. The use of lower doses of ritonavir significantly increased the levels of saquinavir and indinavir while allowing for twice-daily dosing.

Several companies also developed new formulations of existing drugs in an attempt to overcome some of the problems encountered with the original formulations. Hoffman-LaRoche developed an "improved" version of saquinavir (Fortovase) and GlaxoSmithKline developed fosamprenavir (Lexiva) to replace amprenavir (Agenerase). Interestingly, Hoffman-LaRoche is now moving back to the original Invirase formulation of saquinavir (with a new 500-mg tablet) because it is better tolerated than the Fortovase version when the drug is combined with ritonavir. Other companies have also developed new dosage forms, such as Agouron (Pfizer) with a 625-mg nelfinavir (Viracept) formulation.

Another strategy to simplify dosing regimens was to combine different drugs into a single pill. The first was Combivir, which is a combination of zidovudine (Retrovir, AZT) and lamivudine (Epivir, 3TC). In developed countries this is usually only possible when one company makes all of the drugs. Although even this is changing with the recent announcement by Bristol-Myers Squibb and Gilead Sciences that they will combine tenofovir (Viread), emtricitabine (Emtriva), and efavirenz (Sustiva) into a single, once-daily pill. In the developing world market, where much of the drug supply is produced by Indian generic manufacturers, fixed dosed combinations are much more common.

Yet another strategy that was explored, because of the complexities of taking protease inhibitors, was to start people naive to antiretroviral therapy on an induction phase, which consisted of at least 3 drugs. After their viral loads were undetectable for a number of months, patients switched to a maintenance phase of 2 drugs. But a French study and a US study both showed that participants who tried this approach had viral load rebounds more rapidly than participants who started and continued on a 3-drug regimen.

The commercial availability of genotypic and phenotypic resistance testing provided another advance as a way to understand which drug(s) in a treatment regimen was no longer active. However, interpretation of the resistance tests as a means of selecting a new regimen remains problematic even today. These interpretation algorithms are usually put together by a group of experts based on the most recently available data; however, since new data is released constantly, these algorithms are always slightly behind the most current knowledge.

In the early years of HAART, the appearance of body shape changes such as buffalo humps, enlarged bellies, sunken cheeks, and loss of fat in the arms and legs among people with HIV were attributed to the protease inhibitors. Additionally, many people on the protease inhibitors had elevate cholesterol and triglyceride levels, as well as elevated liver enzymes. These factors and the results from the Dupont DMP 006 study showing that etavirenz (Sustiva) was superior to indinavir, resulted in a very rapid shift in how the protease inhibitors were used. Instead of being used as part of a first-line regimen, they were now considered as second- or even third-line regimens. Even though other studies showed that elevations in triglyceride and cholesterol and body shape changes were also seen with the other classes of drugs and not just the protease inhibitors, the field had moved to using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen as part of first-line therapy.

More recently, a new assay to determine the replication capacity of HIV is being studied. While it remains to be seen how to best use the results from this assay in everyday practice, some of the preliminary results have been intriguing. Results suggest that HIV that is resistant to some drugs, especially 3TC and the protease inhibitors, does not replicate as well as wild-type virus. The implications of these findings are that people who have failed their treatment regimen might consider remaining on their failed regimen as the virus is replicating poorly. However, the flip side of such a strategy is that the virus will continue to mutate and eventually may replicate as well as wild-type virus. Furthermore, the additional mutations may confer cross-resistance with other drugs from the same class.

Another area that is being actively being researched is therapeutic drug monitoring. The goal of this approach is to ensure that specific drug levels are within the target concentration--high enough to achieve maximal viral suppression and avoid drug resistance but not too high (so as to minimize side effects). Similarly, pharmacogenomics is being actively researched. It has been widely known that people of different ethnicity and gender metabolize drugs differently. Pharmacogenonmics might, in the future, help predict who might be at risk for developing side effects or who might require a higher or lower dose of a particular drug.

The recent intriguing results from a couple of small studies using lopinavir and low-dose ritonavir (Kaletra) monotherapy may result in a new paradigm shift. Since the introduction of the protease inhibitors and HAART, the recommendation has always been to start therapy with 3 drugs. If the larger studies confirm the results from the smaller studies, it may be possible to take Kaletra as monotherapy when starting antiretroviral therapy for the first time.

New drugs and especially new classes of drugs are needed to help those with limited treatment options. The approval of the fusion inhibitor T-20 (enfuvirtide, Fuzeon) now means that there are 4 classes of drugs available. Several other new classes of drugs are currently being investigated in clinical studies including the CCR5 antagonists, CXCR4 antagonists, and integrase inhibitors. Furthermore, there are several immune-based therapies and therapeutic vaccines in the clinical trial phase. These therapies, while not acting directly against HIV, may boost the immune system to control HIV and may allow people to stop their antiretroviral therapy for a period of time.

While there have been great advances made in the treatment of HIV in the developed world, not everyone in the US is able to access the new medications and diagnostic tests. Budget cuts and the increasing costs of new therapies and diagnostics now means that many people in the US have no or limited access to these advances. Moreover, the availability of these new medications and diagnostic tests has not transferred to the developing world, where the vast majority of people with HIV live. It is important to continue the advances with new diagnostics and new therapies, but it is vital that people have access to the new technologies or therapies as soon as they are commercially available.

Ben Cheng is the Deputy Director of the Forum for Collaborative HIV Research in Washington, DC (hivforum.org).