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Top 12 HIV and Hepatitis Stories of 2012

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In our last issue for 2012, HIVandHepatitis.com reviews some the year's major HIV and viral hepatitis news highlights. On the HIV front, U.S. treatment guidelines recommended antiretroviral therapy (ART) for all HIV positive people, Truvada was approved for pre-exposure prophylaxis (PrEP), and HIV criminalization and cure research were highlighted at the International AIDS Conference in July. Promising findings were reported for several interferon-free oral regimens for hepatitis C, experimental tuberculosis (TB) drugs showed good results, and the Affordable Care Act remained on track.

 

1. ART for Everyone

On March 27 the U.S. Department of Health and Human Services (DHHS) released an updated version of its Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, recommending that antiretroviral treatment should be offered to everyone diagnosed with HIV.

The DHHS panel's decision was primarily based on "increasing evidence showing the harmful impact of ongoing HIV replication on AIDS and non-AIDS disease progression" -- occurring well before a person's CD4 T-cell count reaches a dangerously low level -- but they were also influenced by the growing body of data showing that ART can prevent HIV transmission.

The DHHS recommendation remains controversial, however, as some clinicians and advocate think we do not yet know enough about the long-term risks of antiretrovirals, or whether starting treatment above 500 cells/mm3 will offer significant benefits.

2. Truvada Approved for PrEP

On July 16 the U.S. Food and Drug Administration (FDA) approved Truvada -- Gilead Sciences' tenofovir/emtricitabine combination pill -- for pre-exposure prophylaxis to prevent sexual transmission of HIV.

Matt Sharp, who served as a community representative on the FDA panel, wrote about the vote and its implications.

Approval wasbased on a growing body of evidence showing that tenofovir/emtricitabine can lower the risk of HIV acquisition if taken every day. The iPrEx study of gay and bisexual men (plus a small number of transgender women) and the Partners PrEP and TDF2 studies of heterosexual men and women in Africa showed that once-daily Truvada PrEP dramatically reduced the incidence of new infections. Some studies -- such as the Fem-PrEP trial for heterosexual women -- have not produced impressive results, but data presented at this year's Retrovirus conference (CROI 2012) showed that excellent adherence and adequate drug levels are keys to PrEP's effectiveness.

Like early ART, PrEP is controversial. While it appears highly effective for selected high-risk populations, some have raised concerns about the difficulty of ensuring good adherence, use by people who unknowingly already have HIV, which can lead to resistance, long-term side effects, and cost and access issues.

In September the San Francisco Department of Public Health launched a PreP Demo Project at City Clinic, aiming to enroll 300 HIV negative gay/bisexual men and transgender women. A similar project in Miami will enroll 200 participants. Other PrEP demonstration programs are or soon will be underway in New York City, Washington, DC, Los Angeles, Chicago, and Oakland.

3. Integrase Ahoy!

Integrase inhibitors -- which block with integration of HIV genetic material into the host cell chromosome -- are among the most well-tolerated antiretroviral drugs, likely because they do not interfere with any known human cell functions.

On August 27 the FDA approved Stribild -- formerly known as the Quad -- Gilead Sciences' new single-tablet regimen containing the integrase inhibitor elvitegravir, the novel boosting agent cobicistat, and tenofovir/emtricitabine (the drugs in Truvada). The DHHS Antiretroviral Guidelines panel issued a statement in September indicating that Stribild is now included as an alternative option for people starting HIV treatment for the first time.

Phase 3 studies showed that Stribild suppresses HIV viral load as effectively as either Atripla (Gilead's tenofovir/emtricitabine/efavirenz singe-tablet regimen) or ritonavir-boosted atazanavir (Reyataz), a widely used protease inhibitor. Further analyses showed that Stribild matches these regimens for people across baseline HIV viral load and CD4 T-cell levels and is effective and well-tolerated through 96 weeks.

In June Gilead submitted applications for the approval of elvitegravir and cobicistat as single agents.

Not far behind in the pipeline is ViiV Healthcare's integrase candidate dolutegravir, which was submitted for approval in the U.S., Canada, and Europe in December.

In Phase 3 trials dolutegravir -- which can be taken once-daily without a booster -- demonstrated potent antiviral activity and a good safety profile in both treatment-experienced and previously untreated people with HIV.

ViiV and its collaborator Shionogi are also working on a nano-suspension formulation of the next-generation integrase inhibitor S/GSK1265744, which has a half-life of 20-50 days after a single injection, suggesting that once-monthly or even less frequent dosing may be possible.

4. The Treatment Cascade

The so-called "treatment cascade" was actually first introduced in December 2011, but became widely known during 2012.

According to the Centers for Disease Control and Prevention (CDC), among the estimated 1.2 million people living with HIV in the U.S., about 80% have been tested and know their status, 62% have been linked to care, 41% remain in care, 36% start antiretroviral treatment, and only 28% maintain good adherence to an effective regimen and achieve undetectable HIV viral load.

Another analysis published in January found that less than half of people living with HIV in the U.S. are receiving recommended regular medical care including antiretroviral treatment. A later CDC analysis reduced the viral suppression figure to just 25%.

At this year's CROI Rick Elion from George Washington University School of Medicine explained the cascade of care and why it presents a challenge to the ideal of treatment as prevention. 

In advance of the conference, the International Association of Physicians in AIDS Care (IAPAC) released new guidelines for improving entry into and retention in care for people with HIV, as well as optimizing adherence to antiretroviral therapy.

5. Search for a Cure for HIV

The quest for a cure for HIV hit the headlines in 2010 at the International AIDS Conference in Vienna, and the past 2 years have seen an intensification of effort and early signs of progress.

Matt Sharp provided a recap of cure-related research presented at CROI 2012, including stem cell transplants for HIV positive people with lymphoma, CCR5 gene therapy, and releasing HIV from its latent state.

In advance of the International AIDS Conference (AIDS 2012) in July, the International AIDS Society launched its first strategy for advocacy and research towards a cure for HIV, developed over the past 2 years by an international working group of experts in the field.

That conference featured 3 notable cure-related presentations. Daniel Kuritzkes and Timothy Henrich reported on 2 HIV positive men who underwent bone marrow transplants for lymphoma using "reduced intensity" chemotherapy that allowed them to remain on ART. The men show no traces of HIV after 2 to 3.5 years.

Charline Bacchus and Asier Saez-Ciron described a group of French HIV patients known as the VISCONTI cohort who started ART during the earliest stage of infection and so far appear to be controlling the virus 6 years after interrupting treatment.

Nancie Archin and David Margolis showed that the histone deacetylase inhibitor vorinostat (Zolinza, also known as SAHA) interferes with a mechanism that allows HIV to remain latent in resting CD4 T-cells, offering the potential to flush out the virus.

Sharon Lewin from Monash University in Melbourne gave an overview of cure-related highlights presented at AIDS 2012.

6. High HIV Rates among Black Gay Men

African-American gay and bisexual men in U.S. cities have a significantly higher likelihood of becoming infected with HIV, despite the fact that they do not engage in more high-risk sex or drug use, according to studies presented at the International AIDS Conference and in an HIV theme issue of The Lancet.

Alan Guttirez interviewed Gregorio Millett from the CDC and Sheldon Fields from Florida International University about HIV disparities among black gay and bisexual men and how they might be overcome.

A CDC HIV Surveillance Supplemental Reportreleased in December found that the HIV incidence rate among young men who have sex with men increased by 22% between 2008 and 2010, with more than half of new infections occurring in young black gay men. The report also contained some good news: the rate of new infections among African-American women decreased by 21%.

7. HIV Criminalization

Criminalization of people living with or at risk for HIV gained increased attention this year.

In February, agroup of international civil society experts and advocates released a new statement opposing criminal prosecution of people with HIV. The HIV Medicine Association followed suit in November.

A report released by the Global Commission on Drug Policy in June showed that the war on drugs is a major factor sustaining the worldwide HIV/AIDS epidemic among drug users and their sexual partners. This was exemplified at the end of 2011 when the U.S. Congress reinstated a ban on using federal funds for needle exchange harm reduction programs, as discussed by Laura Thomas of the Drug Policy Alliance.

Similarly, the Global Commission on HIV and the Law Human released a report ahead of the International AIDS Conference describing how laws that criminalize HIV transmission, drug use, and sex work -- as well as policies that perpetuate inequality and violence against women and girls, gay men, and transgender people -- hinder effective response to the worldwide HIV/AIDS epidemic.

Activists interrupted the AIDS 2012 opening press conference to protest U.S. regulations barring sex workers and drug users from entering the country to attend the conference, demanding "nothing about us, without us." Conference attendees also heard from Nick Rhoades, who was convicted of criminal transmission of HIV in Iowa, even though his viral load was undetectable, he used a condom, and his accuser did not contract the virus.

Cyd Nova reviewed 2 reports from the United Nations and World Health Organization and collaborators recommending decriminalization of sex work as part of efforts to decrease HIV/AIDS in Asia and toreduce the vulnerability of sex workers to HIV and other sexually transmitted infections.

8. Hepatitis B Treatment Long-term Benefits

A growing body of evidence shows that nucleoside/nucleotide antiviral therapy for chronic hepatitis B can reduce long-term negative outcomes such as liver cirrhosis, liver cancer, and death.

According to studies presented at the AASLD Liver Meeting and published in the Journal of the American Medical Association, treatment with antivirals including lamivudine (Epivir-HBV) and entecavir (Baraclude) can reduce the risk of developing hepatocellular carcinoma, including cancer recurrence after successful resection.

Similarly, a study described in the The Lancetin December found that treatment with tenofovir (Viread) remained safe and effective over 5 years, and people who achieved sustained virological response experience regression of fibrosis and cirrhosis.

9. Interferon-Free Hepatitis C Regimens

Direct-acting antiviral agents for hepatitis C have ushered in a new era of treatment, but the first approved drugs -- boceprevir (Victrelis) and telaprevir (Incivek) -- must be used with pegylated interferon and ribavirin.

Interferon-free, all-oral regimens are on the horizon, however, with data for several combinations presented at the EASL International Liver Congress in April and the AASLD Liver Meeting in November.

Among the regimens with the most promising data so far, Gilead Science's HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir (formerly BMS-790052)produced sustained virological response (SVR) rates in the 90% to 100% range for treatment-naive patients. Gilead has taken heat from advocates for declining to further test this promising regimen.

At last year's Liver Meeting researchers reported that sofosbuvir (then known as PSI-7977) plus ribavirin produced 100% sustained response at 12 weeks in previously untreated people with HCV genotypes 2 or 3. The dual regimen did not work so well, however, for treatment-experienced patients or those with genotype 1. Data presented at CROI 2012 showed that while all participants saw a rapid decline in HCV RNA and had undetectable viral load at the end of the 12-week course of treatment, almost all genotype 1 prior null responders relapsed soon thereafter, resulting in a low cure rate.

As reported at this year's AASLD meeting, investigators tested a 12-week triple regimen of sofosbuvir plus ribavirin plus GS-5885, Gilead's HCV NS5A inhibitor candidate. All treatment-naive patients and prior null responders had undetectable viral load at the end of treatment and 4 weeks after the end of therapy. Post-treatmentweek 4 is too soon to determine whether participants are cured, but these results are promising. Sofosbuvir plus GS-5885 without ribavirin is also under study.

Bristol-Myers Squibb has also tested a 12-week triple regimen of daclatasvir, the HCV protease inhibitor asunaprevir (formerly BMS-650032), and the non-nucleoside polymerase inhibitor BMS-791325. A small study showed up to a 94% response rate at 12 weeks post-treatment for previously untreated genotype 1 patients.

Other promising interferon-free regimens include:

  • Boehringer Ingelheim's protease inhibitor faldaprevir (formerly BI 201335) plus non-nucleoside polymerase inhibitor BI 207127 plus ribavirin (SOUND-C2).
  • Abbott's ritonavir-boosted HCV protease inhibitor ABT-450 plus NS5A inhibitor ABT-267, with or without non-nucleoside polymerase inhibitor ABT-333 (AVIATOR).
  • Roche/Genentech's protease inhibitor danoprevir (formerly RG7227) plus nucleoside polymerase inhibitor mericitabine (formerly RG7128) plus ribavirin (MATTERHORN).

10. Hepatitis C Treatment for HIV/HCV Coinfected

The first direct-acting antiviral drugs for hepatitis C were approved in 2011, but their indications do not yet include people with HIV.

Coinfected people experience faster liver disease progression and do not respond as well to interferon, so they are in urgent need of better treatments. Challenges of treating this population include drug-drug interactions with antiretroviral therapy and the potentially for greater side effects.

At CROI 2012 researchers presented data showing that adding one of the first-generation HCV protease inhibitors -- boceprevir (Victrelis) or telaprevir (Incivek) to pegylated interferon/ribavirin increased the likelihood of 12-week sustained virological response (SVR12) for HIV/HCV coinfected patients. Response rates approached those of people with HCV alone, and adverse events were not significantly worse. Further boceprevir data were presented at EASL 2012 and final telaprevir SVR24 data were presented at AASLD 2012.

Liz Highleyman discussed treatment of HIV/HCV coinfected individuals with Douglas Dieterich and Kenneth Shermanin a CROI interview for IFARA.

In February Merck warned that interactions between boceprevir and certain antiretrovirals could reduce concentrations of both drugs to potentially ineffective levels. However, no cases of HIV breakthrough were observed in the Phase 2b boceprevir trial presented at CROI, so the clinical significance of this interaction is unclear.

Researchers at CROI presented further data on boceprevir drug-drug interactions, as well as interactions with simeprevir and daclatasvir -- neither of which appear to be clinically relevant. Sofosbuvir interaction and efficacy data were presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in September.

11. New TB Therapies -- Finally!

Tuberculosis (TB) remains one of the leading causes of death for people with HIV worldwide. Multidrug-resistant and extensively drug-resistant TB (MDR-TB and XDR-TB, respectively) are a growing global problem, but no new TB drugs have been approved for many years.

In 2012, the drug development pipeline looks more promising. At the International AIDS Conference researchers reported that atriple regimen containing the experimental drug PA-824, the established TB drug pyrazinamide, and the widely used antibiotic moxifloxacin -- dubbed PaMZ -- showed potent activity in a short randomized study.

Another study, described in the New England Journal of Medicinein June, found that the experimental antibiotic delamanid (OPC-67683)demonstrated good activity against highly-resistant TB, clearing infection in more than 40% of Phase 2b trial participants. Researchers at AIDS 2012 reported that delamanid does not interact with the widely used antiretrovirals tenofovir and lopinavir/ritonavir (Kaletra).

Researchers at ICAAC 2012 reported that the nitroimidazole drug TBA-354, under investigation by the TB Alliance, showed potent activity against Mycobacterium tuberculosis in vitro and in animal studies.

Finally, in late November the FDA Anti-Infective Drugs Advisory Committee gave a favorable opinion on Janssen/Tibotec's request for accelerated approval of its investigational tuberculosis drug bedaquiline (also known as Sirturo, formerly TMC207) for treatment of MDR-TB. The FDA is not required to follow its advisory committees' recommendations, but it usually does so.

12. Obamacare Still Alive

The Patient Protection and Affordable Care Act -- popularly known as "Obamacare" -- has been subject to controversy ever since it was enacted in March 2010.

The Kaiser Family Foundation outlined the benefits of the Affordable Care Actfor people living with HIV, including prohibition of lifetime insurance coverage limits and state programs to provide coverage for people with pre-existing conditions. Matt Sharp described his own experience as a person with HIV who is now able to obtain health insurance thanks to the new law.

On June 28 the U.S. Supreme Court upheld the individual mandate provision of the Affordable Care Act by a 5-4 margin, but declined to require states to expand their Medicaid programs. Advocates generally praised the ruling, but said the law could actually make it more difficult for some low-income individuals to obtain care.

Republicans campaigned against the Affordable Care Act in the run up to the November 2012 election. However, the re-election of President Barack Obama and Democratic gains in Congress raise the likelihood that the law will go into effect as schedule in 2014, despite resistance from some states.

12/27/12