- Category: HIV Treatment
- Published on Tuesday, 27 December 2011 00:00
- Written by Liz Highleyman
In our last issue for 2011, HIVandHepatitis.com reviews some the year's major news highlights. HIV prevention garnered the most headlines, with studies showing that antiretroviral therapy (ART) prevents transmission and pre-exposure prophylaxis (PrEP) works -- at least for some people some of the time. On the hepatitis C front, the first new direct-acting antiviral drugs were approved, ushering in a new era of more effective treatment.
1. AIDS at 30
An overarching theme of the year was the 30th anniversary of AIDS, an opportunity to take stock of the remarkable progress over the past 3 decades as well as work yet to be done.
The anniversary is dated from the first medical report about the epidemic. The June 5, 1981, issue of Morbidity and Mortality Weekly Report (MMWR) included an article about a strange cluster of Pneumocystis pneumonia (PCP) cases among previously healthy gay men in Los Angeles. The July 4 issue described 2 dozen cases of PCP and a rare cancer, Kaposi sarcoma, in California and New York. The first 2 MMWR reports of AIDS are included in The Body's comprehensive archive of articles on the history of the HIV/AIDS epidemic.
2. Treatment is Prevention
The biggest HIV news of 2011 involved findings that were widely anticipated and already informing clinical practice and personal decisions, but data from a large randomized controlled trial removed any doubt: HIV treatment isHIV prevention.
HIV Prevention Trials Network (HPTN) study 052 enrolled 1763 mostly heterosexual serodiscordant couples in 9 countries. HIV positive partners were randomly assigned to either start ART immediately or wait until their CD4 cell count fell below 250 cells/mm3.
The results -- first announced in May, presented with much fanfare at the International AIDS Society (IAS) conference in Rome in July, and published in the August 11, 2011, New England Journal of Medicine-- showed that the risk of transmission fell by 96%, with 4 new infections among partners of promptly treated participants vs 35 among partners of people who waited.
The study's findings were widely hailed as support for increased efforts to expand HIV testing and access to ART both in the U.S. and worldwide, but some experts cautioned that the results do not apply to gay men or injection drug users, and advocates have expressed concern that HIV positive people might be compelled to start treatment before they're ready.
3. PrEP Ups and Downs
Pre-exposure prophylaxis, better known as PrEP, continued to be a major story this year, following the first announcement of findings from the iPrEx trial in late 2010.
As described in more detail at this summer's IAS meeting, iPrEx enrolled nearly 2500 HIV negative gay and bisexual men and a small number of transgender women in 6 countries. They were randomly assigned to take once-daily oral tenofovir/emtricitabine (Truvada) PrEP or placebo, and also received free condoms, risk-reduction counseling, and frequent HIV testing.
PrEP reduced the risk of acquiring HIV by 44% overall (36 new infections among men receiving PrEP compared with 64 among those taking placebo). Risk reduction reached 92% for men with detectable blood drug levels, indicating good adherence.
The TDF2 and Partners PrEP trials, also presented at the IAS meeting, showed that PrEP also reduced the risk of infection for heterosexual men and women and heterosexual serodiscordant couples in Africa. In TDF2, HIV incidence was 63% lower among people who used daily tenofovir/emtricitabine; in Partners PrEP, infection risk fell by 62% among people using tenofovir alone and by 73% among those using the combination.
But there are indications that PrEP may not work as well for women. In the Partners PrEP tenofovir/emtricitabine arm, women showed a risk reduction of 62% compared with 83% for men. The Fem-PrEP study of daily tenofovir/emtricitabine for heterosexual women in Africa was halted early due to lack of efficacy, as was an arm of the VOICE trial testing tenofovir alone (the tenofovir/emtricitabine combination is still being evaluated in that study). A recent study suggested that different tenofovir and emtricitabine levels in vaginal and anal tissue may contribute to the disparity.
While PrEP appears effective for selected high-risk groups, questions remain about inconsistent results across trials, as well as concerns about suboptimal efficacy in real-world use, long-term drug toxicities, emergence of drug resistance, and cost and access. This debate will no doubt continue into 2012, as Gilead Sciences has recently requested FDA approval of Truvada for prevention.
4. Single-tablet Regimens -- the Future of ART
Single-tablet regimens -- ideally one pill once-daily -- are likely to be the future of HIV therapy, at least for people who start treatment with potent ART and do not have extensive drug resistance. Single-pill combos improve convenience, encourage good adherence, and reduce insurance co-pays.
In August the FDA approved the new single-pill regimen Complera, containing tenofovir/emtricitabine and the NNRTI rilpivirine. Studies showed that the drugs in Complera work as well as those in Atripla (tenofovir/emtricitabine/efavirenz), but with fewer neuropsychiatric side effects.
In October Gilead requested FDA approval of its 4-in-1 Quad pill, which contains the new integrase inhibitor elvitegravir boosted with cobicistat (a novel pharmacoenhancer) plus tenofovir/emtricitabine. Data from Phase 3 trials showed that the Quad is non-inferior to both Atripla and ritonavir-boosted atazanavir plus tenofovir/emtricitabine.
The following month Gilead announced that it is working with Janssen/Tibotec to develop the first protease inhibitor-based single-tablet regimen, containing darunavir (Prezista) boosted with cobicistat plus emtricitabine and GS 7340 (a pro-drug of tenofovir).
Together, these 3 coformulations will provide single-tablet options for all major classes of antiretroviral drugs -- NNRTIs, integrase inhibitors, and protease inhibitors.
5. Search for a Cure for HIV
The quest for a cure for HIV really hit the headlines in 2010 following the International AIDS Conference in Vienna, but this year has seen an intensification of effort and some early signs of progress.
In late 2010 researchers reported that Timothy Brown -- better known as the "Berlin Patient" -- still had no detectable HIV 4 years after receiving a bone marrow transplant from a donor with the natural CCR5-delta32 mutation, which means their cells are missing one of the coreceptors HIV uses for entry. In 2011 Brown remained HIV-free as has become an active advocate for cure research.
At the Conference on Retroviruses and Opportunistic Infections (CROI) in March, researchers presented findings from a proof-of-concept study using altered CD4 T-cells that have the CCR5 gene deleted using a zinc finger nuclease. In this small study, 5 out of 6 men on ART with poor CD4 recovery despite undetectable viral load experienced a sustained average increase of 200 cells/mm3 after infusion of the altered cells. HIVandHepatitis.com contributor Matt Sharp described his participation in the study
At the ICAAC meeting in Chicago in September, investigators reported that some participants receiving CCR5-deleted CD4 cells maintained viral suppression for a few months after interrupting ART.
In April a group of researchers, treatment advocates, and regulatory officials met in Baltimore to discuss how to advance cure-related research. Topics included what markers would be considered evidence of progress towards a functional cure or viral eradication, and the ethics of clinical trials in an era of effective ART. Three months later the National Institutes of Allergy and Infectious Disease announced $14 million in new funding for research on strategies to eliminate persistent HIV.
In December, experts meeting in St. Maarten discussed the latest research on HIV eradication, focusing on agents that can activate resting T-cells and force hidden HIV genetic material to begin producing new viruses, which can then be attacked by the immune system and antiretroviral drugs.
6. AIDS Turning a Corner, but Inadequate Funding Threatens Progress
At a high level United Nations meeting in June, in a report commemorating the 30th year of AIDS, and in its annual World AIDS Day report, UNAIDS announced that the epidemic had reached a turning point.
Nearly half of the 14 million HIV positive people eligible for ART in low- and middle-income countries -- more than ever before -- had access to life-saving drugs in 2010, up from just over one-third in 2009.
ART has prevented an estimated 2.5 million deaths since the mid-1990s, according to the World AIDS Day report, and HIV incidence and AIDS-related mortality have fallen to their lowest levels since the height of the pandemic.
Given the latest findings on treatment as prevention, researchers and policy-makers have expressed optimism that an end to the epidemic -- with "zero new HIV infections, zero discrimination, and zero AIDS-related deaths" -- is feasible, and Secretary of State Hilary Clinton's announced in November that an "AIDS-free generation" should be a priority of U.S. international aid efforts.
But such progress is threatened by the global economic crisis. UNAIDS said that donor funding for HIV/AIDS decreased by 10% during 2010, and the Global Fund to Fight AIDS, Tuberculosis and Malaria cancelled its forthcoming round of funding and is focusing on emergency allocations only due to inadequate resources.
7. First Direct-Acting Hepatitis C Drugs Approved
Years of research came to fruition this year as the first direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) were approved in May. The newly approved drugs -- boceprevir (Victrelis) and telaprevir (Incivek) -- are both HCV protease inhibitors and were approved for use with pegylated interferon plus ribavirin.
Pivotal Phase 3 studies showed that boceprevir or telaprevir added to standard therapy significantly increase the likelihood of sustained virological response, and many patients can be cured with a shorter duration of therapy. The American Association for the Study of Liver Diseases (AASLD) updated its hepatitis C treatment guidelines in October to incorporate the new drugs.
2011 also saw the first data from studies of the new DAAs in HIV/HCV coinfected people. At CROI in March and the AASLD Liver Meeting in November, researchers reported that telaprevir improves response rates for HIV positive people who are either not yet on ART or are taking efavirenz or boosted atazanavir regimens.
In a late-breaker presentation at the annual meeting of the Infectious Diseases Society of America (IDSA) in October, investigators reported that boceprevir, too, significantly increased response rates for coinfected people on boosted protease inhibitor-based ART.
While boceprevir and telaprevir are currently only indicated for use with interferon-based therapy, all-oral DAA regimens are the wave of the future.
Several studies presented throughout the year, and especially at the Liver Meeting, showed promising findings for various interferon-free DAA combinations. In the ELECTRON study, 100% of treatment-naive genotype 2 or 3 patients achieved sustained response with the HCV polymerase inhibitor PSI-7977 plus ribavirin, and in another study the HCV protease inhibitor asunaprevir (BMS-650032) plus the NS5A inhibitor daclatasvir (BMS-790052) cured 90% of difficult-to-treat genotype 1 prior null responders.
8. HBV Treatment Long-term Benefits
This year saw little research presented on new therapies for chronic hepatitis B, but some presentations at the AASLD Liver Meeting provided further information about the long-term benefits of current potent antivirals.
One study showed that patients who achieve HBV DNA suppression on entecavir (Baraclude) have a lower risk of liver failure, hepatocellular carcinoma, and death compared with non-responders.
Extended follow-up of Gilead's Study 102 and 103 revealed that most patients who maintain viral suppression on tenofovir (Viread) showed improvement in liver histology -- including regression of cirrhosis -- at 5 years.
9. Hepatitis B and C Both More Common than Estimated
Typically cited numbers of people with hepatitis B and C may actually be lower than actual rates, according to research reported this year.
A meta-analysis published in September found that the estimate of 4 million people with hepatitis C derived from the National Health and Nutrition Examination Survey (NHANES) is an underestimate because it left out groups with higher rates, including incarcerated individuals, homeless people, and active duty military personnel. Adding these populations puts the estimate within the range of 5 to 7 million.
Studies indicate that the largest proportion of people with hepatitis C are "Baby Boomers" who may have become infected decades ago and are only now developing advanced disease. An analysis presented at the AASLD Liver Meeting found that universal, routine screening of people born between 1945 and 1965 regardless of traditional risk factors might detect more than 800,000 unsuspected infections and would likely be cost-effective.
Finally, according to a systematic review described in the November 22 advance online edition of Hepatology, the number of foreign-born (especially Asian and Pacific Islander) individuals in the U.S. with chronic hepatitis B may be considerably higher than earlier estimates -- perhaps as high as 2.2 million.
10. Shorter TB Treatment -- but Not Yet for HIV Positives
Tuberculosis (TB) remains one of the leading causes of death for people with HIV worldwide, but TB treatment in this population remains challenging due to interactions with antiretroviral drugs, poor tolerability, and other complicating factors.
Data presented at CROI in March and in the October 20, 2011, New England Journal of Medicine showed that the optimal timing of antiretroviral therapy for HIV positive people varies based on degree of immune deficiency.
The CAMELIA, ACTG A5221, and SAPIT trials showed that immediate ART for people undergoing TB treatment with low CD4 T-cell counts (below 50 or 200 cells/mm3) significantly reduced the risk of progression to AIDS or death. However, people with relatively high CD4 counts were at greater risk for immune reconstitution inflammatory syndrome (IRIS) if they started ART early.
Data from a study of latent TB infection in HIV negative people, presented at the American Thoracic Society meeting in May and published in the December 8, 2011, New England journal of Medicine, showed that a regimen of isoniazid plus rifapentine administered once-weekly for 3 months prevented active TB disease better than daily isoniazid monotherapy for 9 months.
The CDC recommended the shorter latent TB regimen in December, but the Department of Health and Human Services antiretroviral therapy guidelines panel cautioned that the abbreviated combination regimen is not suitable for people being treated for HIV, since data about interactions with antiretroviral drugs are not yet available.
However, a study published in the July 7, 2011, New England Journal of Medicine showed that the 3-month isoniazid/rifapentine regimen worked as well as extended isoniazid monotherapy for HIV positive people who had a relatively high CD4 cell counts and were not yet on ART.
And a Few Runners Up
Two other topics -- aging with HIV and when to start ART -- continued to generate a considerable amount of interest in 2011, as they did in 2010 and before. They did not make the Top 10 because by now they have become central aspects of the HIV/AIDS discussion and no longer "news."
HIV and Aging
Several studies published this year have shed further light on apparent premature aging and age-related conditions such as cardiovascular disease, neurocognitive impairment, and bone loss among people with HIV.
In late November the American Academy of HIV Medicine (AAHIVM), the American Geriatrics Society, and the AIDS Community Research Initiative of America (ACRIA) jointly released the first clinical guidelines for managing older patients with HIV.
When to Start ART
Updates to U.S. and European antiretroviral treatment guidelines presented in October did not change thresholds for ART initiation, which remain at 500 and 350 cells/mm3, respectively.
Evidence continues to confirm the benefits of starting ART below 500 cells/mm3. The HPTN 052 prevention trial described above, for example, also found that people who started ART immediately experienced 41% fewer clinical events than those who waited until their T-cells dropped below 250 cells/mm3.
But data on treatment above 500 cells/mm3 are mixed. Critics are concerned about long-term toxicities, drug resistance, treatment burnout, and other potential drawbacks.
On the eve of World AIDS Day, the New York City health department rekindled the debate when it announced a new policy of offering immediate ART upon diagnosis of HIV regardless of CD4 count, similar to a policy adopted by San Francisco in 2010.
XMRV Chronic Fatigue Link Appears Broken
Finally, a major story this year concerned a retrovirus distantly related to HIV known as xenotropic murine leukemia virus-related virus, or XMRV.
In October 2009 Vincent Lombardi and Judy Mikovits from Whittemore Peterson Institute (WPI) and colleagues reported in Science that nearly 70% of people with chronic fatigue syndrome (CFS) carried XMRV in their peripheral blood cells, while most unaffected individuals did not.
Several ensuing studies produced mixed findings, but research published this year yielded more definitive negative results. The May 31, 2011, advance online edition of Science featured 2 studies -- one by pioneering HIV researcher Jay Levy -- showing no association between XMRV and CFS, leading the researchers to suggest probable laboratory contamination; the journal issued an "Editorial Expression of Concern."
Then, as described in the September 22 online edition of Science, researchers at 9 laboratories -- including the FDA, CDC, National Cancer Institute, and WPI -- evaluated identical sets of blinded samples from the same CFS patients and healthy donors using a variety of different tests failed to find replicable evidence of XMRV or related retroviruses in CFS blood samples.
The authors of the 2009 report published a partial retraction in the September 22 issue, and Scienceissued a full retraction in December. WPI dismissed Mikovits and she did a short stint in jail for unauthorized removal of lab notes. Nevertheless, she was invited to continue her work under the auspices of W. Ian Lipkin at the National Cancer Institute. Many chronic fatigue patients continue to support Mikovits and her work, hoping for confirmation of a viral cause that might finally point to effective treatment -- potentially including HIV drugs.