2012 promises a number of changes and advances in the way we treat and prevent HIV infection. There is growing enthusiasm for widespread use of antiretroviral therapy (ART), regardless of CD4 count, both for treatment and prevention. New drugs and co-formulations are coming this year that will expand treatment options and simplify drug regimens, especially for initial therapy. At the same time, political and economic realities may prevent us from being able to implement broad-scale treatment and prevention efforts, and the coming of generic drugs, while cost-saving, may put limits on our choices of antiretroviral drugs.
San Francisco and New York City now recommend ART for everyone with HIV, regardless of CD4 count and viral load. Current U.S. treatment guidelines already come close to that aggressive standard. They recommend ART for anyone with a CD4 count below 500, and say that everyone else should consider treatment. Treatment is also recommended at any CD4 count for people with additional conditions, including pregnancy, HIV-associated nephropathy (HIVAN), hepatitis B or C, older age, high viral load, rapid CD4 decline, and high risk for heart disease.
In the minds of many HIV experts, ART is now the "default" -- recommended unless there's a good reason not to treat. Reasons why not to treat? People who aren't ready or willing to start should wait until they are. Some people have no way to pay for treatment, an increasingly common scenario even in the United States. We don't know what to do with "elite controllers" -- people whose viral loads are already undetectable without therapy. Assuming normal and stable CD4 counts, it would be hard to show a benefit to starting ART in those individuals.
How did we get to this point, where ART is recommended for virtually everyone else? First, we're recognizing that HIV isn't just a disease of immunosuppression due to CD4 decline. Untreated HIV has consequences even for people with high CD4 counts, due to the inflammation and immune activation caused by ongoing replication of the virus. Shutting off viral replication may help to reduce the long-term risk of conditions such as heart disease, cognitive decline, loss of bone density, and malignancies by reducing HIV-associated inflammation.
We also know that treating people with HIV lowers their risk of infecting others. In fact, the HPTN 052 study demonstrated that ART was 96% effective at preventing transmission to negative partners, a far greater efficacy than we've seen with any other form of prevention so far, including condoms, circumcision, microbicides, vaccines -- probably even "abstinence." Put simply, if everyone with HIV were on treatment with an undetectable viral load, we would see virtually no new cases.
Evidence of the benefit of early ART is clear, but the decision to treat early must also consider the cost of therapy, in order to weigh the costs against the benefits. Once-daily regimens are now the norm; a growing number of single-tablet regimens (STRs) are becoming available; tolerability and safety are high. Weighing the financial cost against the benefits is more complicated, since it involves economics and politics rather than science. This is where the prevention benefits of ART become so important. Some people may be unwilling to pay for universal ART for individuals, but if universal treatment can slow or even stop the epidemic, perhaps they'll see it as money well spent. (At least, that's what they should be thinking!)
Things are good with respect to initial ART, and there's promise for continued improvement. We now have two single-tablet regimens available, Atripla and Complera, with the "Quad" pill coming soon, and additional co-formulated products and STRs in development. Before long, there may be an STR for almost everyone starting therapy, regardless of which nucleoside analog backbone they're using and whether they're starting ART using a non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor. The co-formulations are likely to benefit treatment-experienced people too, either by allowing use of an STR or by reducing pill burden. For example, taking Norvir as a separate "booster" won't be necessary when the new booster, cobicistat, is approved and combined with Reyataz and Prezista. There's also the possibility that we'll begin to see use of Selzentry or other CCR5 antagonists as part of first-line regimens. People with high CD4 counts who haven't started ART are more likely to have R5-tropic virus, the kind that's required for use of this class of agents. The availability of less expensive tropism assays and once-daily CCR5 antagonists may make this an appealing strategy in the future.
The coming of generics is the wild card. The generic versions of Zerit, Videx, Retrovir, and Combivir have had little impact because they're not preferred drugs, but when Sustiva goes generic, everything could change. With a preferred agent potentially costing a fraction of the cost of its brand name equivalent, it may be hard to justify paying more for the shiny new STRs. Will people have to go back to taking 3-pill regimens to save money, while the STRs languish on pharmacy shelves? Only time will tell. The coming of generic ART is clearly a mixed blessing: On the one hand, who can complain about cheaper HIV drugs at a time when thousands of Americans are on waiting lists for treatment? On the other hand, a move from an STR to a 3-pill mixture of generic and brand name drugs will feel like a step in the wrong direction.
The pipeline for new antiretroviral agents is focused on first-line treatment for one obvious reason: that's where the money is. The efficacy and tolerability of current therapy means that most people do well on their initial regimens and stay on them for a long period of time. Drug companies are far more interested in developing drugs for the large first-line therapy market than for the small number of people with highly resistant virus who are waiting for new drugs.
But there are still people with highly resistant virus, and who's to say we won't see the emergence of resistance to integrase inhibitors and other new agents in the future? Fortunately, there are a few drugs still being developed for treatment-experienced patients, including drugs with novel mechanisms of action, such as the elusive attachment inhibitors (drugs that block the first stage of viral entry).
In the past, I rarely talked about anything "beyond ART," because there was so little to say. That has changed in recent years. While no one should volunteer for a bone marrow transplant to be cured of HIV, the experience of "the Berlin patient" tells us that cure is conceivable, and the topic of cure has been a much bigger focus of scientific conferences and research spending than in years past. We've even seen some corporate interest in this area: for example, Sangamo BioSciences is attempting to modify human CD4 cells to make them uninfectable using zinc finger nuclease technology. We're still a long way from a cure, but it's moved from the realms of science fiction to science.
I should also mention what I'll call "ARP" (for "antiretroviral prevention"). There's now strong evidence that antiretroviral agents can be taken by HIV-negative people, either orally (as pills) or topically (as microbicides) to prevent infection. While many argue that condoms do the job for far less money, our 50,000 new cases per year tell us that our current approaches aren't working. If people who won't wear condoms would take pills or use microbicidal lubes to stay negative, that's money well spent. The unanswered questions have to do with finances and implementation: Who will pay for biomedical forms of prevention, and who will provide it?
We may be approaching an important turning point in the way HIV care is delivered, and the uncertainty is both promising and scary. If fully implemented, the Affordable Care Act may improve health care for a large number of uninsured Americans. However, it could also threaten the quality of HIV care if it leads to weakening of the Ryan White CARE Act, the source of a network of HIV centers providing high quality, multidisciplinary medical and social services to people with HIV throughout the country. Even privately insured people benefit from Ryan White, since they may get their care at HIV centers of expertise that wouldn't exist without the program. Ideally, the Ryan White program should serve as a model for what medical care could be like for all Americans. But policymakers could ignore that, instead transitioning HIV care to Medicaid-funded clinics with little or no HIV expertise, at a time when the already underfunded Medicaid program is targeted by budget cutters in Washington.
It's an exciting time in the history of the HIV epidemic, with outstanding treatment options that keep getting better, and prevention breakthroughs that could have a major impact on the future of the epidemic. However, we're also in the middle of a global financial crisis, and more importantly, a political crisis, in which a large proportion of citizens reject virtually any form of government spending and believe that every dollar they earn is their own to keep. Of course it's not about the money; it's about having the right priorities and political will. Though costly, ART is a highly cost-effective way to treat HIV infection and prevent its spread. We spend far more money on foolish things, with little to show for our spending.
I wish I could conclude by saying that the future of the HIV epidemic will be guided purely by science and sound, evidence-based health care policy, but that may not be the case. Far too much depends on economics and politics, which we'll be hearing a lot about in 2012.
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