Treatment challenge

Highly active ART (HAART) reduce AIDSrelated mortality and morbidity. Has transformed HIV/AIDS from a lifethreatening disease to chronic illness. Improved life expectancy of PLWHA.

Projected mean age at death for patient diagnosed at the age of 30 with CD4 of 400cell/ml in wellresourced setting is 75 years old. Only 7 years less than non-HIV population. Comparable with effect of cigarette smoking.
- Nakagawa F et al. AIDS 2011

In low-income country, 28 additional years among patients diagnosed at age 35. Still as high as non-HIV population in that country.

- Mille EJ et al. Ann Intern Med 2011;155:209-16

Aging of the HIV-positive population is an unexpected development in the history of HIV/AIDS. From opportunistic infections and AIDSrelated malignancies to occurrence of disease in people with mild or moderate immune deficiency. - Non-AIDS morbidity and mortality. The focus of HIV medicine is shifting successful treatment beyond CD4 and/or viral load.

Non-infectious comorbidities that are common among aging persons in the general population have emerged as important cause of death. Non-AIDS related malignancies, cardiovascular disease, and liver toxicity

32%

34%

8%

1999-2000 (N = 255)

10%

16%

AIDS related Liver related CVD related NADM Other/unknown

2009-2011 (N = 548)

39%

22%

9%
20% 10%

Weber R, et al. AIDS 2012. Abstract THAB0304.

AIDS related Liver-related CVD related NADM Other/unknown

HAART side effects

Opportunistic infections

Viral hepatitis STDs

Stigma

Psychological issues

Non-AIDS defining malignancies (NADM). Cardiovascular diseases. Chronic hepatitis co-infections B and C. HIV- associated neurological disease (HAND).

HIV-associated-Non-AIDS (HANA) conditions

HAART associated with a reduced incidence of the two major AIDS-associated malignancies Kaposis sarcoma and high-grade non-Hodgkin lymphoma. Twice the risk of developing a non-AIDS defining cancer than the general population Immunodeficiency (i.e. low CD4 cell count) may not to be the sole crucial factor. - Lifestyle habits, co-infection with oncogenic viruses and longevity Higher in men and advanced stage of AIDS

Hodgkin lymphoma Lung cancer Hepatocelluar carcinoma Vulvar and vaginal intraepithelial neoplasia Anal cancer

Unexpected increase in HIV-associated Hodgkins disease Aggressive disease clinically and histologically. Poorer outcome. 80-100% are EBV-positive.

Pre-HAART - median survival of 12 years, despite chemotherapy. BEACOPP regime + HAART - complete response rate of 100%, overall survival of 83% at 2 years ABVD regime + HAART - overall survival of 76% at 5 years

Increased several fold compared with agematched and gender-matched populations. Usually diagnosed with locally advanced or metastatic disease. - Similar outcome compared to non-HIV population.

Increased risk in HIV patients, occurred at younger age. Underlying chronic Hepatitis B and C. Alcoholism Similar outcome in non-HIV population

Individuals who practice receptive anal intercourse. Increasing number of cases being reported. HAART does not decrease the incidence. Chemoresponsive - equivalent to non-HIV patients.

Rates are significantly lower than in the nonHIV. HAART or their HIV status did not influence - PSA levels - clinical presentation - tumor grade, stage Management and treatment outcome similar to HIV-negative counterpart

Treatment with antiretrovirals did not appear to have an impact on cancer rates. Generally, higher CD4 counts is associated with lower risk of NADM. Studies have shown that most patients with NADC and well controlled HIV viremia can be managed similarly; and with comparable outcome to their HIV-negative counterparts.

HIV infection is pro-artherogenic;

- increased systemic inflammation - hypercoagulation - decreased vascular reactivity.

Changes in lipid profile;

- decreases in serum total serum cholesterol and HDL - increases in serum triglycerides and LDL

Direct consequences of both chronic viremia and of persistent immune activation:

Anti Retroviral Agent Protease inhibitor (PI)

Potential adverse CVS effect Central obesity TC, LDL-C, TG; Insulin resistance TG Insulin resistance cellular oxidative metabolism systemic inflammatory biomarker platelet activation TC, LDL-C

NRTIs stavudine

- abacavir NNRTIs - efavirenz

Triant et al. J Clin Endocrinol Metab. 2007; 92(7): 25062512

HIV patients are at higher risk of developing CVD complication. Routine CVD screening and prevention measures should be part of routine care for all HIV-infected persons.

Independently associated with an increased risk of progression to AIDS or death, despite a similar use of antiretroviral therapies Patients with dual infection may be less likely to achieve a CD4 count rise of at least 50 cells/mL within 1 year of starting HAART HIV viral load response to therapy was similar

Progression is likely to occur more frequently and at a faster rate (2030% of immunocompetent individuals with HCV will progress to cirrhosis over an average of 1530 years) Coinfected patients have comparably higher levels of HCV viraemia are inversely correlated with the CD4 cell count Spontaneous clearance occur in < 15% of patients

Use of HAART: i. Associated with better hepatic outcomes in HIV/HCV-coinfected patients ii. Slower fibrosis progression rate than those with detectable HIV RNA The risk of severe hepatotoxicity with HAART is increased for HIV/HCV-coinfected patients with advanced (METAVIR stage 3 or 4) fibrosis

HCV therapy should be offered to all eligible patients regardless of CD4 counts Initiating HCV therapy early is potentially advantageous for the subsequent management of the patient with HIV infection HCV can be eradicated in almost half of patients who undergo combination HCV therapy.

Data suggest that HAART favorably affects the course of HCV in HIV-infected patients. HAART decreases the rate of death due to liver disease. HAART should not be withheld from HIV/HCV-coinfected persons dues to fears of toxicity. Overall reluctance by patients and providers to initiate HCV therapy have made management of chronic HCV infection a major challenge in the HIV-infected population.

The natural history of HIV infection does not seem to be influenced by hepatitis B Increased rate of antiretroviral-related hepatotoxicity Increased risk of immune-reconstitution hepatitis

Liver damage in HBV infection is immunopathic, so liver disease would be expected to be less severe in HIV infected person. Conflicting evidence At very high levels of viral replication, HBV may have a direct cytopathic effect increased rate of progression to cirrhosis. Progression to liver cancer is more rapid

There are currently seven drugs that have been approved for use against HBV: Four have additional HIV activity: - lamivudine (3TC) - emtricitabine (FTC) - tenofovir (TDF) - entecavir Three are only active against HBV: - interferon, adefovir and telbivudine

Therapy with 3TC, or FTC, without a second anti-HBV-active drug is not recommended Combining 3TC/FTC with tenofovir may reduce the risk of breakthrough resistance CD4 < 350cells/ml start ART CD4 350-500cells/ml combined ART/HBV regime Earlier initiation of ART (CD4> 500cells/ml) should still be considered

BHIVA Guidelines. HIV Medicine (2010), 11, 130

HIV can infect the brain and impair central nervous system (CNS) function. HIV-associated neurocognitive disorders (HAND) remain common despite HAART. Its prevalence is actually increasing, due in part to the longer life expectancy for individuals with HIV.

Nearly 50% of HIV patients demonstrate neuropsychological testing performance that is below expectations. - half are symptomatic and few meet research classification of dementia. Quality of life is greatly affected - disruptions in ability to perform activities of daily living. - adherence to the HAART regime.

Cold Spring Harb Perspect Med. 2012;2(6): a007120

Combination antiretroviral therapy has had a dramatic beneficial impact on the incidence and prevalence of severe forms of HAND Milder form of HAND seems to persist despite HAART Adjuvant therapy being studied: minocycline, selegiline.

HAND incidence correlates with the degree of immune suppression as well as the duration of HIV infection. There has not been any successful adjuvant therapy: to treat the CNS specifically rather than the virus. HAART is still the essential primary approach to treat HAND.

As HIV-infected patients live longer, they are exposed to various co-morbidities which may or may not be directly related to underlying chronic HIV infection. As most of these conditions related to the degree of immune suppression, early initiation of HAART may reduce the risk of developing these co-morbidities i.e CD4 < 500. There appears to be a need for better treatments particularly for neurological problems, non-AIDS defining cancers and cardiovascular complications.