Prevention: A well stocked toolbox
Until recently the tools in the HIV prevention toolbox have included condoms, clean needles and viral suppressive HIV drugs. But looking back, last year may be viewed as a turning point. Significant advances in HIV prevention were seen in vaccine research and new pills and gels for Pre-Exposure Prophylaxis. Furthermore, data published late in 2011 confirmed that after three years, the now famous Berlin Patient was in fact cured of HIV. This year there were no vaccine breakthroughs at CROI, but a new phase of perfecting and planning the use of other prevention tools and advances has begun. The hope is that doing so can at last put an end to the HIV pandemic. Presentations at CROI that the drug Truvada can prevent HIV infection (Pre-Exposure Prophylaxis, or oral PrEP) confirmed that to some degree it works, at least in a clinical trial setting. How to make it work in a real world setting is now the challenge at hand. Already the CDC has produced preliminary guidelines on oral PrEP as studies like the open-label, non-placebo controlled study run their course. Those studies will take several years however. In the meantime, public health experts are debating using oral PrEP outside a clinical trial setting now. It's possible that even before the next set of trials end the FDA will change Truvada's labeling to include oral PrEP, at least so members of at risk communities can get the drug prescribed. Yet there were concerns and questions at CROI about it being used before it's best known how to.
One concern is developing drug resistance in those who take PrEP just after they have unknowingly become HIV infected. PrEP study data showed this still a possibility, especially when so many infected with HIV are on a Truvada regimen. One CROI study, presented by Ume Abbas of the Cleveland Clinic, examined the resistance risks verse the benefits of oral PrEP. It used a mathematical model of large scale distribution of oral PREP to uninfected South Africans along with distribution of an HIV Truvada antiviral regimen for infected ones. The model showed that doing both at once would prevent 838,860 new infections over 10 years and result in only 3300 cases of drug resistance. By comparison, either an antiviral or oral PrEP distribution alone would have far less success. Other researchers at CROI noted a paper recently published in PNAS demonstrating widespread use of oral PrEP would actually lead to less all-around HIV drug resistance. That computer model showed, in short, the following: Access to oral PrEP = fewer HIV infections = fewer on antivirals = less antiviral resistance.
Still, there is the issue of healthy, uninfected people taking HIV drugs. According to several CROI presentations on oral PrEP, one side effect of regularly taking Truvada was slight bone density loss. Truvada has some mild kidney related toxicities as well. And what about the cost? At $36 a day, how many people can afford to take Truvada everyday? What's more, will they even need to? The new CDC guidelines mention that intermittent oral PrEP and "disco dosing" are not yet recommended as they have not been studied in clinical trials. Intermittent oral PrEP trials are underway though. The public relations obstacles for oral PrEP were also discussed at a PrEP strategy meeting at Boston's Fenway Health Center. One participant wondered whether people who are already distrusting of drug companies will blithely take oral PrEP, especially when HIV drugs like Truvada are widely, and justifiably, thought of as having side effects.
Data was also presented on Community Viral Load (CVL). CVL is a measure of HIV viral load from either a location, a demographic group, or patients of a specific clinic. Previous studies have shown that a high Community Viral Load means that community has higher rates of HIV transmissions. Data from several U.S. cities showed that when those in high CVL communities are tested and then treated, rates of HIV infections decrease. That "those that get measured, get managed," according to CVL researcher Moupalis Das. For CVL test-and-treat to work, however, more people in these communities need to realize they are at risk and get tested. The CDC's George Gillet revealed some hurdles in making that happen. His study examined two hotbeds of the epidemic, Black and Latino men seeking sex with men. The study revealed participants sought partners within their own ethnicity or race, mistakenly believing doing so lessened the risk of exposure to HIV. The study also revealed that as members of high risk groups the men did not receive HIV testing through their regular care providers.
Yet despite all the stumbling blocks and unanswered questions at CROI, there was optimism. Optimism that was also fueled by presentations on male circumcision and prevention gels, including one that stops anal transmission. Pile on recent advances in vaccines and the prevention tool box begins to look pretty well stocked. At the moment, however, none of these new, or even old prevention tools provide 100% protection against HIV (some provide even less than 50% protection). Yet using them all together could result in impressive advances in stopping the HIV pandemic. As Robert Grant of the Gladstone Institute put it, "there are many new opportunities available, so now is the moment to invest in them." Thus discussion was rife with calls for a race to the moon commitment to end the pandemic that made CROI seem like a NASA meeting. And there was also good news on the growing size, quality, and new ways to better utilize whats inside the HIV antiviral toolbox.
Antiviral tools: Breakthroughs and new approaches
One way to use whats inside that toolbox is during primary infection (just after becoming HIV infected). Studies have shown that a relatively short course of antivirals during primary infection can lower the long-term viral load set-point, slowing down disease progression toward AIDS. Marlous Grijsen presented data showing that lowering the set point with a 24 week course of antivirals can also delay the need to go on them by two years. At a press conference Marty Markowitz and conference John Coffin commented on Grijsen's data. To take advantage of this early treatment benefit they emphasized the importance of test and treat during primary infection and that it needs to be put into wider practice. Doing so could postpone going on HIV drugs and the later drug toxicities and side effects, as well as the overall cost of treatment.
Whatever the course of treatment, it looks as if there is no added advantage in suppressing HIV with five drugs instead of three. A disappointed Marty Markowitz had hoped to prove that low-level HIV replication could be stopped using more drugs against different viral targets. But although those on the five drug regimen became undetectable sooner, there was no overall added reduction in viral load or differences in t-cells. The bright side? There will be no shift toward a standardized five drug regimen which will also keep side effects and drug costs down. Although the results probably won't sway skeptics and conspiracy theorists who believe the HIV epidemic is a massively contrived plot to profit drug companies.
One clear highlight at this years CROI was the breakthrough on treating HIV/HCV co-infection. The new protease inhibitor telaprevir (TVR) is the first of several that will treat hepatitis C (HCV). When used in combination with standard treatment, the drug can actually cure HCV in about 70% of HIV/HVC co-infected individuals. A previously released study showed a 75% cure rate in just HCV infected individuals. Many in both studies were chronically infected by HCV yet were still able to be cured. At a press conference excited researchers actually sanctioned the use of the C word ("cure") by journalists. FDA approval of TVR is expected sometime this Spring. Other HCV protease inhibitors and later, HCV polymerase inhibitors, will begin to come out regularly after TVR's approval. That means even greater improvements in HCV treatment are not far off.
And speaking of cures, with the recent data confirming that the Berlin Patient is cured of HIV, the quest to wipe it out in everyone else infected seems to have become, along with an HIV vaccine, a holy grail of HIV research. Presentations at CROI in particular showed the grail may be a little closer at hand. Paula Cannon's team will use HIV infected lymphoma patients to repeat the success of the Berlin Patient. That requires an immune system wipe-out, or ablation procedure, and bone marrow transplant that can have high mortality. So, instead, Jay Lalezari of Quest is attempting a "Berlin Patient Lite" gene therapy approach. Lalezari's study hopes to instill and mimic the natural protection HIV long term non-progressors have against the virus. His partial immune makeover involves taking out a subjects t-cells and altering them to stop expressing the cell receptor CCR5 that HIV uses to enter the cells. The cells are then re-infused back into subjects. Then hopefully the new cells will dominate as the older HIV vulnerable cells die or are killed by HIV. When the old cells are gone, HIV, in theory, will not be able to replicate and overtime it will just fade away. The early data on the six study subjects who received the altered cells showed that five have already had increases in t-cell counts of around 200. It remains to be seen if these cells are both functional and impervious to HIV. And as the study subjects remain on HIV meds it will be a while to see if the altered cells control or eliminate HIV. At a press conference the extremely cautious researchers downplayed the significance of the clinical data. It should also be noted that some types of HIV use other receptors like CCR4 to enter T-cells. Other researchers at CROI did present data on altering cells so that they don't express these receptors. But despite all these hopeful efforts and the confirmation of the cured Berlin patient, a cure for everyone with HIV is still a ways off.