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A paradigm shift in the standard of care for the diagnosed HIV population

Patients diagnosed with HIV infection in the U.S. and other major markets are living longer, healthier lives than ever before due to the radical transformation in the HIV standard of care. Over the past decade, starting with the 2006 FDA approval of Gilead’s Atripla, a once-daily single-tablet regimen (STR) for highly active antiretroviral therapy (HAART), many HIV patients have been able to successfully suppress their viral loads to undetectable levels by taking a single once-daily pill. A number of other STRs have reached the market since the launch of Atripla, offering patients increasingly safer and more effective options. These newer STRs, namely Gilead’s Stribild and ViiV’s Triumeq, are regarded by HIV thought leaders, physicians and patients alike as the most important advancement in treatment, largely due to the inclusion of integrase inhibitors, a class with a high barrier to the development of drug resistance and excellent efficacy, safety and tolerability profiles. The effectiveness of these new antiretroviral regimens has fueled a paradigm shift in the lives of the diagnosed HIV patient population. What was once a devastating disease with high mortality rate (over 50,000 peak U.S. deaths in 19951-2) is now largely a manageable chronic condition.

Safer therapies for chronic use in an aging population: a new unmet need

The population of HIV-positive individuals in the U.S. is aging, with 49% of drug treated HIV patients in the U.S. being over the age of 50 (HIV drug treated age demographics were calculated using Symphony health PHAST 2.0 2015 HIV drug prescriptions [green U.S. state map] based on the CDC’s 2013 diagnosed HIV population estimates3 [purple U.S. state map]). The older patient demographic, including those diagnosed with HIV, is also expected to grow notably over the coming decades. The U.S. Census Bureau estimates the population over 65 will double between 2010 and 2050, increasing the likelihood of accompanying age-related comorbidities. Concurrent with the aging HIV patient population in need of treatment is the increase in the already enormous burden placed on the healthcare system. The HIV-positive population will become a larger fraction of the patients requiring age-related care, illustrated by the first confirmed HIV positive case of Alzheimer’s disease4. Further complicating matters, recent reports indicate that the HIV-positive population is at increased risk of age-related comorbidities, with an average of five years earlier onset of comorbidities as compared to HIV negative individuals5. While the exact mechanism responsible for accelerated aging in HIV-positive individuals is poorly understood, the consequences pose a unique challenge for physicians, particularly when the presence of comorbidities influence a patient’s treatment.

Among HIV patients, persistent issues remain, such as access to healthcare, social stigma and notably suboptimal patient adherence, an issue that is affecting the elderly more than the general population6. In 2012-2013, the CDC estimated that only 62% of patients on antiretroviral therapy maintain viral suppression7, highlighting that while the lives of those with HIV infections have improved dramatically over the past 20 years, there is still a need for improvement. As adherence to therapy is one key factor in decreasing the spread of HIV, it is an issue that should be prioritized by managing healthcare professionals, especially for their older patient population who are often not considered still sexually active and are therefore still at risk of transmitting the virus.

New opportunities, new therapies for an aging population

Moving forward, it will be critically important for the HIV pipeline to address the needs of an older patient population who will require lifelong HAART as no functional cure is currently available. A functional cure, which is defined as a therapy that completely eradicates an HIV infection and eliminates the need for life-long HAART treatment, would certainly revolutionize the treatment of HIV patients, though is highly unlikely to reach the market in the near future. The elusiveness of a functional cure is continuously demonstrated in leading scientific journals where all too often, high hopes in combination with great science are met with poor efficacy due to the virus’ keen ability to evade detection and rapidly evolve drug and antibody resistance. The currently available therapies and those on the horizon, however, provide optimism for patients that their evolving needs will be met in the absence of a functional cure.

Several manufacturers are seeking to address key needs of older HIV patients, notably frailty and kidney disease. The long-term use of some HAART regimens is associated with an increased risk of renal toxicity and bone demineralization. One way to reduce the risk of these long-term side-effects is to avoid regimens containing agents that can elevate the risk of damage, such as using nucleoside reverse transcriptase inhibitor (NRTIs) -sparing regimens. Recently, early clinical data suggests ViiV’s integrase inhibitor Tivicay (dolutegravir) may be efficacious as a monotherapy maintenance option for patients who are virally suppressed8-10, signaling a potential new age of NRTI-free regimens. New NRTI-sparing regimens could be especially advantageous for older patients as long-term therapy options, given that these would minimize drug toxicity risks that lead to frailty and kidney disease.

Additionally, Gilead has recently brought three new combination therapies to the market that contain tenofovir alafenamide (TAF), an NRTI with demonstrated improvements in safety over tenofovir disoproxil fumarate (TDF), a key NRTI backbone component in many regimens in the current standard of care. Clinical data submitted for FDA approval of these combinations highlighted statistically significant improvements at 96 weeks post-start of treatment for both bone demineralization and renal toxicity as compared to TDF-containing regimens (Genvoya vs. Stribild, Gilead studies 104 and 11111-13). These results are encouraging for the older HIV population, a group that is already at high risk of renal dysfunction and bone loss, and will benefit the most from even safer drugs.

However, long-term real world evidence will be required to validate the benefits for patients who are faced with taking life-long HAART therapy. Several areas of unmet need remain for manufactures to continue improving the decades of HAART advances already brought to the aging patient population. The hope for the future is that new therapies will continue to decrease the mortality gap, possibly by addressing the chronic inflammation and advanced aging associated with HIV infection, providing a quality of life equal to the broader population.

For a more in depth analysis of the unmet needs of the HIV population, please see our recent reports on Human Immunodeficiency Virus, 2015 Disease Landscape & Forecast HIV G7.

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References:

  1. http://www.cdc.gov/hiv/pdf/library/slidesets/cdc-hiv-surveillance-genepi.pdf
  2. Slide Set: HIV Mortality (through 2010). http://www.cdc.gov/HIV/library/slidesets/index.html
  3. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Atlas. Data are estimates from all 50 states, the District of Columbia, and 5 U.S. dependent areas.
  4. http://www.onenewspage.com/video/20160421/4323433/Longtime-HIV-Survivor-Develops-Alzheimer-Disease-HealthFeed.htm
  5. Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA Gross, Andrew M. et al. Molecular Cell , Volume 62 , Issue 2 , 157 - 168
  6. Gellad WF, Grenard JL, Marcum ZA. A Systematic Review of Barriers to Medication Adherence in the Elderly: Looking Beyond Cost and Regimen Complexity. The American journal of geriatric pharmacotherapy. 2011;9(1):11-23. doi:10.1016/j.amjopharm.2011.02.004.
  7. Crepaz N, Tang T, Marks G, Mugavero MJ, Espinoza L, Hall HI. Durable viral suppression among HIV-diagnosed persons United States, 2012-2013. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 1033.
  8. Rojas J et al. Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: a 24-week pilot study. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
  9. Katlama C et al. Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
  10. Hocqueloux L et al. Simplification for dolutegravir as a mono- or bitherapy maintains high proportion of viral suppression even in highly-experienced HIV-1-infected patients. 15th EACS, 21-24 October 2015, Barcelona. Poster abstract PE8/37.
  11. http://www.gilead.com/news/press-releases/2015/10/gilead-announces-phase-3-results-for-genvoya-elvitegravir-cobicistat-emtricitabine-and-tenofovir-alafenamide-an-investigational-oncedaily-single-tablet-regimen-for-hiv
  12. http://www.gilead.com/news/press-releases/2016/3/us-food-and-drug-administration-approves-gileads-second-tafbased-single-tablet-regimen-odefsey-emtricitabine-rilpivirine-tenofovir-alafenamide-for-the-treatment-of-hiv1-infection
  13. http://www.gilead.com/news/press-releases/2016/4/european-commission-grants-marketing-authorization-for-gileads-fixeddose-combination-descovy-emtricitabine-tenofovir-alafenamide-for-treatment-of-hiv