Optimizing Antiretroviral Treatment

Study BackgroundThe infection of Human immunodeficiency virus (hereinafter referred to as HIV or AIDS virus) was discovered in early 80s of last century. Since then HIV infection has spread world widely. In China, although the AIDS epidemic is still in low prevalence, in specific population and high prevalence in some areas, but the AIDS situation remains very grim.Highly active antiretroviral therapy (hereinafter referred to as ART or HAART) can prolong the lives of AIDS patients, and can improve their quality of life. But it is still worthy for further study that how to optimize antiviral therapy for achieving best efficacy of HAART, especially the question about when to start HAART. In the post-HAART era which HAART was introduced to clinical activities over a decade, the guidance of threshold of HAART initiation is evolving based on the development of the understanding of this disease and its treatment. It was changed from "hit early and hit hard" to the consensus "delayed initiation of HAART till CD4+T lymphocyte count<200 cell/mm3". In 21st century, more and more clinical evidence demonstrate if delayed initiation of HAART till CD4+T lymphocyte count<200 cell/mm3, the incidence of HIV related diseases and mortality in HIV infected patients will be increased. And it is harmful to subsequent immune reconstruction and recovery. Therefore, in recent years, the threshold of HAART is modifying. In developed countries, new guidelines recommend to initiate HAART when CD4+T lymphocyte count<350 cell/mm". In particular, Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents issued by U.S. Department of Health (DHHS) in 2009 recommends starting HAART when CD4+T lymphocyte count at 350-500 cell/mm3. And WHO also modified the guidance in 2009. In this update version, WHO recommends when the CD4+T lymphocyte count<350 cell/mm3, HAART therapy should be initiated. It's really a significant breakthrough. Since, in the past, WHO has been guiding in the developing countries with the recommendation of delayed HAART initiation until CD4+T lymphocyte count<200 cell/mm3. And the Chinese guideline is not changed since it was issued in 2006. It recommends to initiate the HAART till CD4+T lymphocyte count<200 cell/mm3 or CD4+T lymphocyte count<350 cell/mm3 associated with HIV-related illness or symptoms. Exactly when to start HAART treatment, whether CD4+T lymphocyte count 350 cell/mm3 is a better threshold or not, is still a question for further study or discussion.In addition, in post-HAART era, HIV infected patients have a longer lifetime under the effective HAART. But liver-related diseases, especially virus hepatitis became an important cause of death in HIV infected patients. This is due to the similar routes of transmission, hepatitis C virus (HCV) co-infection or hepatitis B virus (HBV) co-infection in HIV infected patients are common. It is very critical to manage and treat HIV/HCV and HIV/HBV co-infected patient for optimizing HAART therapy.In China, there is a high prevalence of HIV/HCV co-infection in HIV infected patients that have been infected through hematogenous route, including intravenous drug use or paid blood collection. And as a country with high HBV epidemic, HIV/HBV co-infection is common as well. Learning more about the HCV or HBV co-infection in HIV infected population will be conductive to optimize HAART.This study is designed to study the above mentioned two key points in HAART strategy through systematic review of the literature, in order for providing scientific evidence to optimizing the anti-HIV therapy.Study Objective1. Systematic review and analyze the best threshold for HAART initiation;2. Systematic review and analyze the HAART in HCV or HBV co-infected HIV patients.Study MethodThis study is a systematic review of the literature. Retrieve automatically all relevant published English academic articles in PubMed database by using search strategy. Meanwhile, use manual search strategy to retrieve the relevant articles referred by retrieved publications. Inclusion and exclusion criteria are set for article screening in order to target articles which meet study requirements. Analyze the articles by listing all the relevant data extracted from the articles under different topics.Study ResultThere are 29 articles selected regarding to threshold of HAART initiation. Among these articles, 22 analyzed the Hazard Ratio (HR), including AIDS new illness/death HR and other HR within different thresholds. The major aspects are the impact of base line CD4 + T lymphocyte count when HAART is initiated on AIDS/Death and immune reconstitution. The study found that in HIV infected patients, compared with HAART initiated at CD4 + T lymphocyte count> 350 cell/mm3, if HAART started at 200-350 cell/mm3, it will increase the risk of AIDS new illness/death, and also may increase virologic failure, and occurrence of other serious complications, such as anemia, peripheral neuropathy, renal insufficiency, and etc. Meanwhile, in the study of taking CD4 + T lymphocyte count 500 cell/mm3 as the threshold of HAART initiation, it demonstrated that compared with starting HAART at CD4 + T lymphoid 350-500 cell/mm3, if HAART is initiated at CD4 + T lymphocyte count greater than 500 cell/mm3, the risk of AIDS new illness/death will also be reduced. In the aspect of immune reconstitution, HAART initiated at CD4+T lymphocyte count> 350 cell/mm3 showed profit to the immune reconstitution. If HAART is initiated at CD4 + T lymphocyte count> 350 cell/mm3, CD4 + T lymphocyte count can be maintained at a platform of CD4 + T lymphocyte count 800 cell/mm3 after the treatment. And conversely in the group of CD4 + T lymphocyte count 200-350 cell/mm3, CD4 + T lymphocyte platform is significantly lower, average at 500-600 cell/mm3.In the study of HIV/HCV co-infection, a total of 38 articles are included. They studied from the following aspects respectively:Indicators of HIV infection, including the impact of HAART treatment on death or disease progression in HIV/HCV co-infected patients, and the impact of HIV/HCV co-infection on CD4+T lymphocyte count; liver fibrosis in HIV/HCV co-infected patients, including risk factors associated to liver fibrosis or cirrhosis in co-infected patients and the impact of HAART on liver fibrosis; and in addition, when to initiate HAART in HIV/HCV co-infected patients. This study found that, in the research of survival, mortality (liver disease related mortality) of HIV/HCV co-infected patients, HAART treatment is significantly related with reducing the patients'mortality and prolonging patients' survival. Compared with HIV mono-infection, HIV/HCV co-infection significantly increases the likelihood of the occurrence of liver fibrosis or cirrhosis. In HIV/HCV co-infected patients, the study also showed low level of CD4+T lymphocyte count, HAART treatment (including HAART treatment time and regimen) are associated with the occurrence and progression of liver fibrosis and cirrhosis. Low CD4+T lymphocyte count level will increase the incidence of serious hepatic fibrosis and cirrhosis, and HAART generally does not affect and even may help to reduce the occurrence of liver fibrosis. But we should pay attention on the choice of different HAART regimen, for example protease inhibitor (PI) is benefit to the occurrence of liver fibrosis and cirrhosis, but Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) (nevirapine for example) will increase the incidence of severe liver fibrosis. This is due to the drug related hepatotoxicity of different drugs.Regarding to the study of HIV/HBV co-infection, there are 17 articles met the research requirement. They analyzed the risk factors of death and disease progression in HIV/HBC co-infected patients; the impact of HIV/HBV co-infection on mortality; the impact of HIV/HBV co-infection or HBV status on HIV viral suppression and/or CD4+T lymphocytes count; and the use of HBV-active HAART regimen in the treatment of HIV/HBV co-infected patients. This study reviewed all articles selected, and found that compared with HIV mono-infected patients, the HIV/HBV co-infected patients have higher risk of death, including AIDS-related mortality and non-AIDS related mortality, especially the mortality associated with liver diseases. HBV infection status is not significantly associated with HIV viral suppression and CD4+T cell immune response under HAART therapy. In addition, HAART is a long term therapy, and the drug choice must be considered carefully, for example HAART regimen should include anti-HBV therapy (HBV-active) drugs such as lamivudine (3TC) and tenofovir (TDF). Also in the HIV/HBV co-infected patients, we must avoid the use of drugs with high liver toxicity in HAART regimen, such as nevirapine (NVP), ritonavir (RTV) and etc.Study Conclusion1. This study demonstrated if HAART is initiated at CD4+T lymphocyte count> 350 cell/mm3, in particular, if set the threshold as CD4+T lymphocyte count 500 cell/mm3, in HIV infected patients, incidence of HIV-related morbidity and mortality will be decreased, quality of life can be enhanced, and immune reconstitution and immune function maintenance will be improved as well. However, whether CD4+T lymphocyte count 500 cell/mm3 is a more optimal threshold of HAART, it still needs to be confirmed by further randomized clinical trials. 2. In the post-HAART era, liver-related diseases have become the major cause of death in HIV infected patients. HIV/HCV and HIV/HBV co-infection increase the risk of death in these patients. Our strategy should be:early detect, initiate HAART rationally, treat HCV infection or HBV infection, reduce the morbidity of liver-related diseases and relevant mortality, and prolong life span in these patients.