Viruses - antiretrovirals - Cancer Therapy Advisor

What are the key principles of preventing viruses – antiretrovirals?

Highly active antiretroviral therapy (HAART) is the key principle in treating human immunodeficiency virus (HIV). HAART is defined as the use of at least three drugs from two different mechanistic classes (Table I).

Table I.

Nucleoside reverse transcriptase inhibitors (NRTIs)	Non-nucleoside reverse transcriptase inhibitors (NNRTIs)	Integrase strand transfer inhibitors (INSTIs)	Protease inhibitors (PIs)	Entry inhibitors (EIs)
Abacavir	Delavirdine	Elvitegravir*	Atazanavir	CCR5 inhibitor: Maraviroc
Didanosine	Efavirenz	Raltegravir	Darunavir	Fusion inhibitor: Enfuvirtide
Emtricitabine	Etravirine		Fosamprenavir (previously amprenavir)
Lamivudine	Nevirapine		Indinavir
Stavudine	Rilpivirine*		Lopinavir
Tenofovir			Nelfinavir
Zalcitabine			Ritonavir
Zidovudine			Saquinavir
			Tipranavir

*In clinical trials with expectation of new approval.

For HIV treatment-naive patients, the combination of two NRTIs with a NNRTI, a PI, an INSTI, or an EI (specifically, maraviroc) is considered the standard of care. For treatment resistant HIV patients, three to five antiretrovirals (ARVs) may be used and should include at least two (preferably three) new ARVs.

Human immunodeficiency virus replication

HIV recognizes cells with a CD4 receptor and a chemokine receptor (CC chemokine receptor 5 [CCR5] and/or CXC chemokine receptor 4 [CXCR4]). HIV attaches to both receptors via an external protein, glycoprotein (GP) 120. The GP 120-CD4/chemokine receptor interaction exposes HIV GP41 (composed of helical region [HR] 1, 2 and fusion peptide).

Fusion peptide enters the CD4 cell membrane and this step signals HR 1 and 2 to form a six-hairpin structure resulting in HIV cell entry or fusion. After HIV fusion is complete, the reverse transcriptase enzyme transcribes HIV from a RNA virus to proviral DNA. Proviral DNA is integrated (via the integrase enzyme) into the human DNA genome. Large polypeptides are released into the cytoplasm and upon exiting from the CD4 cell; the protease enzyme cleaves the gag and gag-pol polypeptides into a new infectious virion.

Currently, there are twenty-five antiretrovirals marketed in the United States.

Customizing an ARV to the patient is key to HAART success. This includes an assessment of individual patient variables: co-morbid illnesses, drug-drug interactions, pharmacogenomic variables (HLA-B*5701), expected toxicities/adverse drug reactions, genotypic/phenotypic analyses, and adherence.

What are the key conclusions for available clinical trials and meta-analyses that inform control of viruses – antiretrovirals?

Early HAART initiation, when CD4 counts are between 350-500 cells/mm³,has demonstrated significant reductions in acquired immune deficiency syndrome (AIDS)-associated morbidity and mortality (Table II).

Table II.

Reference	Initiate	Recommend	Consider
2011 Panel on Antiretroviral Guidelines for Adults and Adolescents	Any AIDS-defining illness	CD4 count between 350-500 cells/mm³	CD4 count >500 cells/mm³
	CD4 count <350 cells/mm³	Pregnant females not meeting HAART initiation criteria
	Regardless of CD4 count: HIV-associated nephropathy Hepatitis B virus (HBV) coinfection, if HBV treatment is indicated
2010 recommendations of the International AIDS Society–USA panel		Regardless of CD4 count: Symptomatic HIV disease Pregnancy HIV-1 RNA >100,000 copies/mL Rapid decline in CD4 cell count, >100 cells/mm³/year Active hepatitis B or C coinfection Active or high risk for cardiovascular disease HIV-associated nephropathy Symptomatic primary HIV infection Risk for secondary transmission is high, e.g., serodiscordant couples	Asymptomatic, CD4 cell count >500 cells/mm³
		CD4 count <500 cells/mm³

What are the consequences of ignoring key concepts related to control of viruses – antiretrovirals?

Some of the most severe complications related to poor virologic control include:

Death: The following website allows the practitioner to use patient specific data (age, route of infection [e.g., injection drug use or not], CD4+ count, HIV PCR [copies/mL], and historical AIDS-defining illnesses) to determine a 1 to 5 year estimated probability of AIDS-defining illness or death: www.art-cohort-collaboration.org.
Opportunistic infections.
AIDS related cancers including Kaposi’s sarcoma, Non-Hodgkin’s lymphoma, and cervical cancer.
Non-AIDS related cancers: increased association with CD4 counts less than 500 cells/mm³.
Cardiovascular disease.
Chronic kidney disease: HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal disease in HIV-infected patients. HIVAN primarily occurs in patients of African descent. Co-morbid illnesses (e.g., diabetes, hypertension, and hepatitis C co-infection) contribute to the onset of chronic kidney disease in HIV positive patients. All HIV positive patients should be screened at initiation of care with a dipstick for proteinuria, serum creatinine, and calculation of the glomerular filtration rate.
Poor prognosis in patients co-infected with hepatitis B and C.

Summary of current controversies.

Current controversies regarding antiretrovirals are as follows:

Cardiovascular disease (with or without metabolic syndrome)

In a large retrospective VA-based cohort study, HAART-related cardiovascular disease was not demonstrated. Moreover, a significant mortality reduction resulted after HAART initiation.

A large prospective cohort study (Data Collection on Adverse Events of Anti-HIV drugs [D:A:D]) to evaluate the incidence of myocardial infarction in patients with HIV demonstrated an increased cardiovascular risk. Patients receiving PIs for greater than 6 years were at the highest risk (relative risk [RR] 1.17 [95% CI 1.12-1.23]). Specific PIs including lopinavir/ritonavir and indinavir have the highest risk.

In a separate study (the French Hospital Database), fosamprenavir was also associated with an increased risk of myocardial infarction (OR 1.53 [95% CI 1.21-1.94 per year]). No increased cardiovascular risk was demonstrated in patients using NNRTIs as part of their HAART regimen.

With regards to the NRTIs, didanosine and abacavir increase the myocardial infarction risk by 49% and 90%, respectively, when recent use (defined as use within the last 6 months) was included (D:A:D). Avoidance of these agents is recommended when patients have the highest Framingham risk (20% within 10 years) for a future cardiovascular event.

In the D:A:D cohort, controlling for cardiovascular risk factors including: age, BMI, calendar year of event, cardiovascular history, cohort, family history, gender, HIV transmission group, race/ethnic group, or smoking status did not affect the results (RR 1.16 [95% CI 1.10-1.23]). When a history of diabetes, hypertension, or dyslipidemia was controlled for in the analysis, myocardial infarction risk decreased (RR 1.10 [95% CI 1.04-1.18]).

In contrast to the D:A:D, the HIV outpatient study did not find an increased cardiovascular risk with any antiretrovirals. However, increased cardiovascular risk was demonstrated in HIV patients with a CD4+ count less than 350 cells/mm³. These data are in concordance with the International AIDS Society Panel, which has recommended initiation of antiretroviral therapy (regardless of the CD4+ count) in patients with a cardiovascular history with aggressive management of modifiable risk factors.

Osteopenia, osteoporosis, and osteomalacia

Bone disease has been documented in HIV positive patients before and after HAART initiation. Factors associated with decreased bone mineral density and reduced vitamin D concentrations include the following: chronic kidney disease, HAART (e.g., atazanavir, efavirenz, ritonavir, and tenofovir), and duration of antiretroviral use.

Acute renal failure

Tenofovir may lead to proximal tubular dysfunction and renal failure necessitating regular monitoring for renal insufficiency before and after initiation.^{Indinavir and atazanavir may lead to nephrolithiasis. Atazanavir may lead to acute interstitial nephritis.}

Immune reconstitution inflammatory syndrome

After HAART initiation with a positive virologic and/or immunologic response, immune reconstitution inflammatory syndrome (IRIS) may occur and is defined as the following:

The occurrence of a new infection.
The recurrence or increased severity/frequency of an infection.
The decreased response to standard treatment of a prior infection.

Non-infectious IRIS events have also been reported (e.g., rheumatologic and cancers). IRIS may be fatal and appears to be associated with a baseline CD4 count (<50 cells/mm³) at HAART initiation.

Controversies in detail.

The benefits and risks of early versus late initiation of antiretroviral therapy are well summarized in the guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Benefits of early antiretroviral therapy:

Reduction in mortality and/or AIDS-related morbidity.
Prevention and treatment of HIV-associated nephropathy.
Prevention of end-stage liver disease complications in co-infected patients with hepatitis B and/or hepatitis C.
Prevention of cardiovascular disease.
Decreased incidence of AIDS-related and non-AIDS related malignancies.
Prevention of neurocognitive decline.
Improved immunologic response in patients greater than 50 years old.
Decreased T-cell activation and inflammation.
Prevention of HIV transmission (mother-to-child, sexual).
Improved quality of life in symptomatic patients.

Risks associated with early antiretroviral therapy:

HAART toxicities.
Decreased quality of life in asymptomatic patients.
Antiretroviral drug resistance in non-adherent patients.
Cost.

The overall antiretroviral benefit to HIV positive patients outweighs any of these risks and treatment should be offered to all patients meeting the recommendations for HAART initiation.

What national and international guidelines exist related to viruses – antiretrovirals?

Gazzard, BG, Anderson, J, Babiker, A. “British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008”. HIV Med. vol. 9. 2008. pp. 563-608.

“Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents”. Department of Health and Human Services. January 10, 2011. pp. 1-166.

Kaplan, JE, Benson, C, Holmes, KH. “Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America”. MMWR Recomm Rep. vol. 58. 2009. pp. 1-207.

Thompson, MA, Aberg, JA, Cahn, P. “Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel”. . vol. 304. 2010. pp. 321-33.

“WHO, Antiretroviral therapy, available from their website”.

What other consensus group statements exist and what do key leaders advise?

Aberg, JA, Kaplan, JE, Libman, H. “Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV Medicine Association of the Infectious Diseases Society of America”. Clin Infect Dis. vol. 49. 2009. pp. 651-81.

Gupta, SK, Eustace, JA, Winston, JA. “Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America”. Clin Infect Dis. vol. 40. 2005. pp. 1559-85.

References

“Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents”. Department of Health and Human Services. January 10, 2011. pp. 1-166.

Cervia, JS, Smith, MA. “Enfuvirtide (T-20): a novel human immunodeficiency virus type 1 fusion inhibitor”. Clin Infect Dis. vol. 37. 2003. pp. 1102-6.

D’Souza, MP, Cairns, JS, Plaeger, SF. “Current evidence and future directions for targeting HIV entry: therapeutic and prophylactic strategies”. JAMA. vol. 284. 2000. pp. 215-22.

Kilby, JM, Eron, JJ. “Novel therapies based on mechanisms of HIV-1 cell entry”. N Engl J Med. vol. 348. 2003. pp. 2228-38.

Thompson, MA, Aberg, JA, Cahn, P. “Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel”. . vol. 304. 2010. pp. 321-33.

Kitahata, MM, Gange, SJ, Abraham, AG. “Effect of early versus deferred antiretroviral therapy for HIV on survival”. N Engl J Med. vol. 360. 2009. pp. 1815-26.

Sterne, JA, May, M. “Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies”. Lancet. vol. 373. 2009. pp. 1352-63.

May, M, Sterne, JA, Sabin, C. “Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies”. AIDS. vol. 21. 2007. pp. 1185-97.

“Antiretroviral therapy cohort collaboration (ART-CC), Lanoy E, May M, et al. Prognosis of patients treated with cART from 36 months after initiation, according to current and previous CD4 cell count and plasma HIV-1 RNA measurements”. AIDS. vol. 23. 2009. pp. 2199-208.

Bonnet, F, Burty, C, Lewden, C. “Changes in cancer mortality among HIV-infected patients: the Mortalité 2005 Survey”. Clin Infect Dis. vol. 48. 2009. pp. 633-9.

Simard, EP, Engels, EA. “Cancer as a cause of death among people with AIDS in the United States”. Clin Infect Dis. vol. 51. 2010. pp. 957-62.

Engels, EA, Pfeiffer, RM, Gordert, JJ. “Trends in cancer risk among people with AIDS in the United States 1980-2002”. AIDS. vol. 20. 2006. pp. 1645-54.

Bruyand, M, Thiebaut, R, Lawson-Ayayi, S. “Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: agence nationale de recherche sur le sida (ANRS) CO3 aquitaine cohort”. Clin Infect Dis. vol. 49. 2009. pp. 1109-16.

Lichtenstein, KA, Armon, C, Buchacz, K. “Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study”. Clin Infect Dis. vol. 51. 2010. pp. 435-47.

Yahaya, I, Uthman, AO, Uthman, MM. “Interventions for HIV-associated nephropathy”. Cochrane Database Syst Rev. 2009. pp. CD007183

Bozzette, SA, Ake, CF, Tam, HK, Chang, SW, Louis, TA. “Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus syndrome”. N Engl J Med. vol. 348. 2003. pp. 702-10.

Bozzette, SA, Ake, CF, Tam, HK. “Long-term survival and serious cardiovascular events in HIV-infected patients treated with highly active antiretroviral therapy”. J Acquir Immune Defic Syndr. vol. 47. 2008. pp. 338-41.

Friis-Moller, N, Sabin, CA, Weber, R. “Combination antiretroviral therapy and the risk of myocardial infarction”. N Engl J Med. vol. 349. 2003. pp. 1993-2003.

DAD, study group, Friis-Moller, N, Reiss, P. “Class of antiretroviral drugs and the risk of myocardial infarction”. N Engl J Med. vol. 356. 2007. pp. 1723-35.

Westring Worm, S, Sabin, C, Weber, R. “Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study”. J Infect Dis. vol. 201. 2010. pp. 318-30.

Lang, S, Mary-Krause, M, Cotte, L. “Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control nested within the French Hospital Database on HIV ANRS cohort CO4”. Arch Intern Med. vol. 170. 2010. pp. 1228-38.

D:A:D, Study Group, Sabin, CA, Worm, SW. “Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration”. Lancet. vol. 371. 2008. pp. 1417-26.

McComsey, GA, Tebas, P, Shane, E. “Bone disease in HIV infection: a practical review and recommendations for HIV care providers”. Clin Infect Dis. vol. 51. 2010. pp. 937-46.

Borderi, M, Vescini, F, Cozzi-Lepri, A. “Prevalence of hypovitaminosis D among HIV+ patients enrolled in a large Italian cohort. [Poster 751]”. Poster presented at the 17th Conference on Retroviruses and opportunistic infections. February 16-19, 2010.

Dao, C, Patel, P, Pals, S. “Assessment of vitamin D levels among HIV-infected persons in the study to understand the natural history of HIV/AIDS in the era of effective therapy: SUN study. [Poster 750]”. Poster presented at the 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA. February 16-19, 2010.

Mueller, N, Fux, C, Ledergerber, B. “High prevalence of severe vitamin D deficiency in cART-naive and successfully treated Swiss HIV patients. [Poster 752]”. Presented at the 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010.

McComsey, G, Kitch, D, Daar, E. “Bone and limb fat outcomes of ACTG A5224s, a substudy of ACTG 5202: a prospective, randomized, partially blinded phase III trial of ABC/3TC or TDF/FTC with EFV or ATV/r for initial treatment of HIV-1 infection. [Oral presentation 106LB]”. Presented at the 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010.

Cooper, RD, Wiebe, N, Smith, N, Keiser, P, Naicker, S, Tonelli, M. “Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients”. Clin Infect Dis. vol. 51. 2010. pp. 496-505.

Chan-Tack, KM, Truffa, MM, Struble, KA, Birnkrant, DB. “Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration's adverse event reporting system”. AIDS. vol. 21. 2007. pp. 1215-8.

Savini, C, James, C, Wilson, S, Martin, H, Szabo, S, Scotto, V. “Case presentation: nephrolithiasis in a patient treated with atazanavir”. J Assoc Nurses AIDS Care. vol. 19. 2008. pp. 225-7.

Ratnam, I, Chiu, C, Kandala, NB, Easterbrook, PJ. “Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort”. Clin Infect Dis. vol. 42. 2006. pp. 418-27.

Murdoch, DM, Venter, WDF, Van Rie, A, Feldman, C. “Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options”. AIDS Res Ther. vol. 4. 2007. -9.

Muller, M, Wandel, S, Colebunders, R, Attia, S, Furrer, H, Egger, M. “Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis”. Lancet Infect Dis. vol. 10. 2010. pp. 251-61.

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