In 2013, the U.S. Department of Health and Human Services (DHHS) expanded their HIV treatment guidelines, recommending the earlier implementation of combination antiretroviral therapy (cART) in adults infected with HIV. The recommendations now call for cART at CD4 counts below 500 cells/mL, while allowing for therapy at CD4 count over 500 cells/mL—moving the U.S. ever closer to universal treatment on diagnosis.
Rationale for Early Therapy
The DHHS decision is supported by mounting evidence that early treatment of HIV is associated with a number of positive outcomes, namely:
- A reduction of HIV-related and non-HIV-related illnesses and deaths.
- Increases in life expectancy, with rates approaching (or even possibly exceeding) that of the general population.
- A continued reduction in the number of HIV transmissions from mother to child.
- Potentially lower incidences of HIV transmission, wherein a lower "community viral load" appears to translate to lower infection rates.
Despite the breadth of the evidence, there still remains some contention as to the "right" time to start therapy.
Many researchers and public health officials believe today that early cART can slow (or even potentially control) disease progression, while reducing the establishment of latent reservoirs where HIV can persist for decades even in the face of successful therapy.
Others, meanwhile, argue that the potential for long-term toxicities is still unknown, and that there is no evidence that early intervention will increase survival time.
What is known is this: initiation of cART before the onset of AIDS (or an AIDS-defining illness) correlates to higher life expectancy. Research from the U.K. Collaborative HIV Cohort Study has shown that initiation of cART below a CD4 count of 200 cells/mL was not only associated with poorer outcomes, but a reduction in life expectancy by as much as 15 years.
Recommendations for Initiation of HIV Therapy
The current adult guidelines, updated by the DHHS in October 2013, include the following recommendations:
- Strong recommendations that cART be implemented in all patients with a CD4 count under 350 cells/mL, or in the presence an AIDS-defining illness.
- Strong recommendations that cART be initiated, irrespective of CD4, in the event of pregnancy, hepatitis B (HBV), hepatitis C (HCV), or HIV-associated kidney disease.
- Strong recommendations that cART be initiated in patients with a CD4 count between 350 and 500 cells/mL, based on the evidence from large-scale, randomized trials and observational studies.
- Moderate recommendations that cART be started at CD4 counts over 500 cells/mL, based on mounting clinical evidence and epidemiological research.
In their February 2013 policy review, the U.S. panel was reportedly split 50/50 on whether to issue "strong" recommendations for cART initiation over 500 cells/mL.
Recommendations for First-Line Therapy in Adults
For previously untreated (a.k.a. "treatment naive") patients, the U.S. panel currently recommends one of seven drug regimens as their "preferred" options for first-line therapy:
- Isentress (ratelgravir) + Truvada (tenofovir + emtricitabine), taken once daily
- Stribild (elvitegravir + cobcistat + tenofovir + emtricitabine), taken once daily
- Tivicay (dolutegravir) + Epzicom (abacavir + lamivudine), taken once daily
- Tivicay (dolutegravir) + Truvada (tenofovir + emtricitabine), taken once daily
- Atripla (tenofovir + emtricitabine + efavirenz), taken once daily
- Reyataz (atazanavir) + Norvir (ritonavir) + Truvada (tenofovir + emtricitabine), taken once daily
- Prezista (darunavir) + Norvir (ritonavir) + Truvada (tenofovir + emtricitabine), taken once daily
The primary rationale for the DHHS "preferred" status includes a regimen's low pill burden, easy dosing schedule, reduced side effect profile, and high barrier to drug resistance.
Since certain conditions may exclude some from taking the preferred options (such as Truvada in patients with renal failure), the DHHS lists 10 "recommended" and eight "satisfactory" alternatives for first-line therapy.
Finally, as the focus increasingly shifts from drug efficacy to drug adherence, there will be greater impetus placed on the use of "all-in-one" fixed-dose combination (FDC) drugs such as Stribild—with one study suggesting that patients receiving a single pill per day are 24% less likely to be hospitalized than those receiving three or more.
Department of Health and Human Services (DHHS). "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." Rockville, Maryland; accessed May 20, 2014.
Department of Health and Human Services (DHHS). "Recommendation on Integrase Inhibitor Use in Antiretroviral Treatment-Naive HIV-Infected Individuals from the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents." Rockville, Maryland; accessed February 18, 2014.
Hogg, R.; Samji, H.; Cescon, A., et al. "Temporal Changes in Life Expectancy of HIV+ Individuals: North America." 19th Conference on Retroviruses and Opportunistic Infections (CROI). March 7, 2013; Seattle; Oral Presentation #137.
Sax, P.; Meyers, J.; Mugavero, M., et al. "Adherence to Antiretroviral Treatment and Correlation with Risk of Hospitalization among Commercially Insured HIV Patients in the United States." Tenth International Congress on Drug Therapy in HIV Infection. November 8, 2010; Glasgow; Oral Presentation #0113.
Charlebois, B.; Das, M.; Porco, T.; and Havlir, D. "The Effect of Expanded Antiretroviral Treatment Strategies on the HIV Epidemic among Men Who Have Sex with Men in San Francisco." Clinical Infectious Diseases. April 15, 2011; 52(8):1046-1049.
Kitahata, M.; Gange, S.; Abraham, A., et al. "Effect of early versus deferred antiretroviral therapy for HIV on survival." New England Journal of Medicine. April 30, 2009; 360(18):1815-1826.
Helleberg, M.; Afzal, S; Kronborg, G.; et al. "Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study." Clinical Infectious Diseases. March 2013; 56(5):727-34.
Sáez-Cirión, A.; Bacchus, C.; Hocqueloux, L.; et al. "Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study." PLoS Pathology. March 14, 2013; 0(3):e1003211.