Some of the most significant contributions in medical history have been made in AIDS research in a relatively short time. In the U.S., in just 14 years, there are sixteen FDA-approved anti-HIV drugs that slow disease progression. But treatments remain complex, less than perfect, and cause side effects -- and AIDS is still with us. New formulations and simpler once-a-day dosages have been developed but there is still room for improvement. Several more drugs from new classes that target the virus differently are in the research pipeline, but beyond that there appears to be a lag in further promising development. A sizeable and growing percentage of people are drug resistant, meaning drugs are less effective. For these people, there is a pressing need for new treatments -- either new, non-cross-resistant members of existing drug classes, or agents that work in different ways. The overall learning curve of HIV treatment has perhaps reached a critical peak; now the time for dealing with the long-term effects of the drugs and research into more effective drugs has come to pass.
With the dilemma of a pressing need for new therapies and drug companies cutting back on research and development, it makes sense that scientists need to concentrate on ways to improve immune function so that we do not have to rely as much on the mediocre, toxic antiviral drugs. There is some good, yet incomplete information on ways to bolster the immune system with immune modulators such as IL-2, that has been studied for years. Vaccine technology and structured treatment interruption are hopeful, yet inconclusive. More advocacy and research needs to be done in this area.
Most of us recognize that the majority of drug resistance is caused by poor adherence. One way to enhance adherence to antiviral therapy is to make drugs easier to take. AZT and 3TC have been combined to make Combivir, and AZT, 3TC and abacavir have been joined to make Trizivir. Both are one pill twice a day. ddI is now made in a once a day enteric coated formulation that will metabolize better. Newer versions of older drugs are also being developed to lower pill burden in order to improve adherence and improve bioavailability.
Viread was the only anti-HIV drug approved in 2001. The drug is looking good in resistant patients, and it only has to be taken once a day! T-20 is an exciting drug reaching a critical phase in development. A new open label study program will offer a small supply of the drug to the most advanced patients in the first part of 2002. Activists wouldn't stand for the company to call the program an expanded access program because of the limited number of slots.
The importance of developing drugs that will work against drug resistant strains cannot be overstated. A few novel nucleoside analogs, DAPD and dOTC, may have activity against some resistant strains. Emtricitabine is also in the pipeline as a once daily regimen but is not effective against 3TC resistant strains.
Second-generation NNRTIs that may retain activity against virus resistant to current agents include TMC120, that looks strong in early Phase I studies, and DPC 083, a cousin to Sustiva. Tipranavir is the leading new protease inhibitor in development that shows activity against many PI resistant strains. Several other protease inhibitors are in early stages of testing that may prove to be less toxic, easier to take, and not cross resistant to older PIs.
Inhibitors of fusion and entry are earlier in development, so it is too soon to know if they work. However, the drugs may perform well together and are encouraging because they won't be cross resistant to older drugs, possibly being more effective at lowering virus levels. Many of the co-receptor inhibitors have to be infused and there are various toxicity problems in early studies, so it is not yet clear just yet how these drugs will play out.
The year holds more positive news on the vaccine front. For the second year there was a Vaccine Conference that didn't necessarily provide dramatic news, but at least was a means to mobilize people working in the field. Most of the attention in prevention vaccines is currently focused on DNA vaccines with various viral vectors as boosters. A number of approaches are moving into production or are in very early safety trials. The Vaccine Trials Network and Walter Reed Army Institute are moving ahead with two other booster vaccines that could go into efficacy trials in 2002-3. Results from the VaxGen trials in gay men and IDUs will be available then too. It still is way too early to tell if any of these will be effective in preventing HIV, but it appears to be a good start. The world is watching and waiting.
In therapeutic vaccines, the most interest is with very early treated individuals and in structured treatment interruption, before chronic infection is established and HIV T-cell help is lost. Merck has initiated trials of its vaccines in HIV positive people and met with community representatives in December 2001 to report on its program.
It used to be that AIDS complications were mostly life threatening opportunistic infections. Today with at least partial viral control and some immune system repair, complications due to therapy have become more prevalent than OIs and malignancies. It is clear that in the long term, HIV drugs are causing problems that are becoming more and more a serious problem. Liver toxicities are seen in 6-7% of people taking HIV medications. A major cause of death in HIV is liver failure. Hepatitis C and long-term antiviral use is the culprit. Metabolic complications remain a puzzling situation but there are more hints as to the cause. In the MAC cohort study 33% of participants reported body fat changes. Metformin, oxymetholone (a testosterone derivative), pioglitazone, and rosiglitazone are promising treatments for lipodystrophy. Serostim is helping with body fat accumulation as well. There seem to be less treatment interventions for lipoatraphy, or loss of body fat in the face and limbs.
Years ago, stopping HIV therapies might have seemed like suicide, but today with growing concern over long-term toxicity this new option is being studied. Therapy interruption is a protocol of stopping and starting HIV drugs in order to relieve the cumulative side effects and maybe kick start the immune system. There is growing evidence that in early infection the strategy may be effective in controlling HIV. However, in the chronically infected, STI appears to not work as well. One promising strategy is the NIH study of heavily treated patients on a 7-day-on, 7-day-off regimen. After 52 weeks there was no resistance seen. There were very low level blips in viral load in a few patients and complete control in the others. Significantly, drug toxicities appeared to be reduced. (See "News Briefs.")
Obviously, drug companies do not like the STI approach because in the end they lose. STI would undoubtedly save on prescription costs and be a godsend in developing countries. As with many areas of research that are new and controversial, researchers are divided over whether it is something to pursue. STI needs to be proven before people decide they can do it outside of the research setting.
Our health care infrastructure is ready to implode as the insurance industry is finding manipulative ways to not cover people who are sick. Quality care for the HIV patient today is complex and expensive. Co-payments and premiums are rising beyond the scope of most people's budget and drug coverage and diagnostics are covered less and less. HIV doctors have cut back in their practices and are closing because the companies will not pay for the specialized treatment required by people with HIV. Insurers are folding and merging, creating fewer options for coverage of quality care. Corporations and businesses have to find cheaper insurance plans that leave out people who need coverage the most. Most frustrating is the fact that AIDS drugs have set the precedent for high pricing seen by pharmaceutical companies, which is driving up the cost of health care. It's also clear that our government has put plans for prescription coverage for the elderly on the back burner, so any plan to fix our nation's pathetic health care system is not even in the picture.
The AIDS Drug Assistance Program (ADAP) is losing funds as interest with AIDS on Capitol Hill wanes. The feds identified $120 million for this year but that amount falls short since last year the budget began $50 million short of what was needed. Since state budgets complete the picture of ADAP funding, they will be pressured to come up with more funds. Given the murky past with some state ADAPs this news is not encouraging. New drugs are increasing the costs, especially high tech agents that are needed for treatment experienced folks.
The recent recession and war against terrorism have certainly changed American's "business as usual" attitude and therefore affected the way we think about AIDS. Now as I watch the AIDS drug pipeline, and the pathetic health care infrastructure, I worry that AIDS has become a thing of the past, only overshadowed by imminent problems.
Thanks to Bill Snow, Jeff Getty, Anne Donneley, and Martin Delaney for information provided for this article.
Matt Sharp is currently a member of two grassroots national groups, Coalition for Salvage Therapy and AIDS Treatment Activists Coalition. He has written extensively on AIDS treatment for the past seven years for the Bay Area Reporter in San Francisco, and AIDS Web sites and newsletters all over the country. Recently transplanted from San Francisco where he was an AIDS treatment educator, activist and advocate, he now resides in Chicago with his partner.