Human immunodeficiency virus disease management in highly active antiretroviral therapy era: A comprehensive review

Human immunodeficiency virus (HIV) is a retrovirus belonging to the family Lentiviruses, which are responsible for chronic and long-lasting infections including the simian immunodeficiency virus (SIV) in monkeys. Since 1981, when the first acquired immunodeficiency syndrome (AIDS) cases were reported, HIV poses a challenge to human beings, and the UNAIDS global estimate reveals that currently more than 33.2 million people are living with HIV infection worldwide. HIV infection leads to variable disease course in different people. The biological basis of this variability in the disease progression is still unknown. Initiation of highly active antiretroviral therapy (HAART) although reduced the mortality, morbidity arising from antiretroviral side effects was a cause of concern. HIV-infected patient care has now shifted from complications arising from opportunistic infections to other causes attributable to HIV pathogenesis and toxic effects of HAART. Monitoring the disease progression and the response to HAART is traditionally carried out using TCD4+ cell counts and HIV/RNA viral load. Many clinical and laboratory markers have been used to estimate disease progression in HIV1 infection. HIV/AIDS after introduction of HAART has taken a different course where people infected with HIV have been considerably living longer due to reduced incidence of opportunistic infections and other AIDS-related conditions. HIV patient care should be multifaceted involving specialist HIV primary care physicians, infectious disease specialists, and emergency physicians considering the ways by which HIV and HAART have changed treatment and management of HIV-infected individuals.

Keywords: Disease progression, human immunodeficiency virus, highly active antiretroviral therapy

Human immunodeficiency virus (HIV) is a retrovirus belonging to the family Lentiviruses, which are responsible for chronic and long-lasting infections including the simian immunodeficiency virus (SIV) in monkeys. HIV type 1 was first described by Barre-Sinnoussi and Gallo in 1983 and later in 1986 Clavel demonstrated HIV type 2 as being responsible for acquired immunodeficiency syndrome (AIDS). ^[1],[2] Evolutionary studies have confirmed that HIV type 1 is more pathogenic than HIV type 2 and has come from monkeys (SIV), whereas the HIV type 2 has evolved from sooty mangabeys (SIV _sm ). Since 1981, when the first AIDS cases were reported, HIV poses a challenge to human beings, and the UNAIDS global estimate reveals that currently more than 33.2 million people are living with HIV infection worldwide. ^[3] HIV infection leads to variable disease course in different people. The HIV disease progression is characterized as rapid, typical, or intermediate and late or nonprogressors. The majority of infected individuals (70-80%) experience intermediate disease progression in which they show HIV/RNA rise, CD4+T-cell decline, and later development of AIDS-related illness in 6-10 years. About 10-15% of the infected patients whose CD4+Tcells rapidly decline and go into AIDS within few years of infection are called rapid progressors. The late progressors (5%) can remain asymptomatic and healthy without showing significant changes in CD4+T-cell counts even for 10 years among them are long-term nonprogressors, who survive for more than 10 years after getting infected. ^[4] The biological basis of this variability in the disease progression is still unknown, although some studies have related the long-term nonprogressors (those infected with HIV type 1 but show no decline in CD4 cell counts) to the presence of defective virus. ^[5] Classically, HIV disease progression is seen as a decline in CD4 cell counts and increase in the plasma HIV/RNA viral load. Due to the chronicity of the disease and the extent of morbidity and mortality it causes, management of such individuals has become a challenge for physicians treating HIV-infected patients. ^[4] HIV infection is associated with destruction of lymphoid tissue and decrease in immune function to fight the entry and elimination of virus from cells.

HIV and HAART

Introduction of HAART in 1995 has been limited to developed nations mostly due to the financial constraints of low socioeconomic countries. ^[6] Fortunately, there was a gradual increase of access to HAART in the developing countries, which carry most of the burden of HIV seropositive individuals. ^[7] Initiation of HAART though reduced the mortality, morbidity arising from antiretroviral side effects was a cause of concern. ^[8] HIV-infected patient care has now shifted from complications arising from opportunistic infections to other causes attributable to HIV pathogenesis and toxic effects of HAART. ^[9] Studies have shown a significant reduction in mortality of HIV-infected individuals for the post-HAART era as compared with pre-HAART era. ^[6] Recent studies have demonstrated that HAART may not be helpful in controlling the virus replication after the acute infection has suppressed the lymphoid system. ^[10] Studies have also demonstrated the role of HIV infection in suppression of thymus, thereby initiating hemostasis and CD4 depletion. ^[11] Decision on when to initiate HAART is traditionally done on the basis of CD4 cell counts. ^[12] Considering the ill effects of HAART regimen, initiation of antiretroviral therapy was planned only for patients with CD4 cell counts <200 mm ³ . With the advent of newer antiretroviral drugs, easy access to infected patients and affordable costs, initiation of HAART is now recommended for patients whose CD4 counts are between 350 and 500 mm ³ . Irrespective of CD4 cell counts initiation of HAART can be taken by the physician treating HIV-infected patients based on the age, type of antiretroviral drug, its adverse reactions, and compliance for long duration of drug regimen by patient. ^[6],[13] Depending on their mode of action, currently five types of antiretroviral drugs are available including the nucleoside reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, protease inhibitors, entry and fusion inhibitors, and the integrase inhibitors. Abacavir, zidovudine, lamuvudine, emtricitabine, didanosine, stavudine, and tenofovir constitute the nucleoside reverse-transcriptase inhibitors. Nonnucleoside reverse-transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. Amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir constitute protease inhibitors. Entry and fusion inhibitors include enfuviritide and maraviroc. Raltegravir acts as integrase inhibitor. Bone-marrow suppression, lactic acidosis, peripheral neuropathy, skin hyperpigmentation and hypersensitivity reactions, pancreatitis, Stevens-Johnsons syndrome, hepatic steatosis, nausea, headache, vomiting, and diarrhea are some adverse reactions of nucleoside reverse-transcriptase inhibitors. Nonnucleoside reverse-transcriptase inhibitors produce psychosis, depression, suicidal tendency, transaminitis, Steven-Johnsons syndrome, hepatic failure, headache, and rash. Toxic effects of protease inhibitors include prolonged PR interval, raised indirect bilirubin, renal toxicity, rash, nausea, diarrhea, and vomiting. Hepatotoxicity, dyslipidemia, hyperglycemia, and intracerebral hemorrhage were also observed in patients under treatment with protease inhibitors. Injection site infection, postural hypotension, abdominal pain, and pneumonia are the complications aroused by treatment with entry and fusion inhibitors. ^{[6],[14],[15],[16],[17],[18],[19],[20]} Adverse drug reaction due to integrase inhibitors includes nausea, head ache, and cardiovascular complications. Either due to infection with HIV or due to opportunistic infections and the adverse action of antiretroviral therapies or in combination, HIV patients on HAART suffer from various complications including endocrine disorders, musculoskeletal diseases, cardiovascular complications, hepatobiliary diseases, psychiatric illness, neurological disorders, renal complications, hematological disorders, and different types of cancer. ^{[12],[15],[21]}

Monitoring HAART

Monitoring HAART therapy and thereby HIV disease progression is done by three methods including the virological, immunological monitoring, and clinical monitoring. Measuring CD4 cell counts at regular intervals constitute immunological monitoring. ^{[13],[22],[23],[24],[25]} Either with or without laboratory support, clinical assessment for the presence of opportunistic infections, side effects of HAART on various system, and presence of immune reactivation inflammatory syndrome (IRIS) can be done by looking for various signs and symptoms. ^[26],[27] To effectively monitor the disease progression and the response to highly active antiretroviral therapy (HAART) in the poor, developing, and economically weak third world countries that carry most of the burden of HIV seropositive patients, it becomes financially overburdened to acquire resources and infrastructure necessary for patient management. ^{[28],[29],[30]} Monitoring the disease progression and the response to HAART is traditionally carried out using CD4+ T cell counts and HIV/RNA viral load. ^[31] Many clinical and laboratory markers have been used to estimate disease progression in HIV1 infection. ^{[32],[33],[34]} Markers of AIDS development include viral markers (plasma HIVRNA load, serum p24 Ag, serum anti-p24 antibodies), surrogate markers(antibodies against p17, gp120, gp41, and nef gene product), and nonspecific markers including CD4+T-cell counts, CD8+T-cell counts, and delayed type hypersensitivity test (DTH). Other alternate markers include elevated serum β2-microglobulin, neopterin (D-erythro-1′,2′,3′-trihydroprpylptrin), dehydroepiandrosterone(DHEAS), serum cortisol, and many others including CRP, ESR, serum albumin, tumor necrosis factor (TNF), interferon-γ, interleukin-2(IL-2), and IL-4. Biochemical parameters including serum albumin, globulin, serum glutamate-oxaloacetate transaminase (SGOT), total protein, total cholesterol, high-density lipoproteins (HDL), low-density lipoprotein(LDL), lactate dehydrogenase (LDH), and creatine kinase (CK/MB) were also evaluated by some studies as useful markers to assess the disease progression and treatment response. ^{[4],[12],[35]}

Studies conducted in the past have demonstrated the role of HIV infection by itself irrespective of HAART therapy can result in the development of metabolic disorders including altered lipid metabolism. ^[36] Previous reports have also suggested the association of cardiovascular disease (CAD), acute cardiovascular events, and HAART therapy. TCD4+cell counts have been proved an incomplete marker after initiation of antiretroviral therapy in assessing the disease progression and treatment response. Considering the above-mentioned factors, research is now being conducted to find some cost-effective, easily performed, and freely available surrogate or alternate markers that can help in assessing the HIV disease progression. ^[6],[12] With the advent of HAART, the quality of life of HIV seropositive patients improved to a greater extent, simultaneously their morbidity and mortality have reduced significantly. Conversely, previous research reports have pointed out the effects of ART on the patients, as well as stressed the need to evaluate various hematological parameters before initiating HAART therapy. ^[4],[22] Previous reports have also suggested the CAD and HAART therapy. Studies have suggested that HIV influences inflammatory processes independent of CD4+T-cell counts and that the viral proteins, including the Tat and Nef, may influence the monocyte functions,that is, cytokine and chemokine production and their survival. Furthermore, few studies have emphasized oxidative stress as a principal mechanism in both the HIV replication and AIDS development. Previous studies have explained the role of HIV infection alone, irrespective of HAART therapy on the development of various metabolic disorders and chronic oxidative stress. ^[37],[38]

CD4 and viralload testing versus system-based management

Introduction of HAART has considerably reduced the mortality in HIV seropositive patients, and we see the number in HIV/AIDS-related deaths has been gradually decreasing. From the time when HIV epidemic was prevalent and people being detected for HIV positivity were on the rise, CD4 T-cell count and HIV/RNA viral load were used to assess their immunological status and infectivity based on virological load. HIV-infected patients were screened for various opportunistic infections depending on the TCD4 cell counts and clinical examination and prophylactic therapy initiated where and when necessary. ^[39] HIV/AIDS, after introduction of HAART, has taken a different course where people infected with HIV have been considerably living longer due to reduced incidence of opportunistic infections and other AIDS-related conditions. Of late,HIV-infected individuals have been bothered by noninfectious complications that need emergency medical attention and care. HIV disease pathogenesis though is complicated, significant research has been done to prove that HIV has the ability to disturb the cell metabolism. Oxidative stressand programmed cell death (apoptosis) can result in accumulation of free radicals and in turn be responsible for prolonged inflammatory activity. HAART has worsened the situation by adding adverse drug reactions to already significant HIV pathogenesis. From being a life-threatening infection, HIV has now emerged as a chronic infection that can influence most of the human systems. Cardiovascular complications, gastrointestinal and hepatic emergencies, pulmonary illness,psychiatric ailments, and hematological, neurological, renal, and oncological complications have been on the rise among HIV-infected patients more so after initiation of HAART therapy. Physicians treating HIV seropositive patients should think beyond opportunistic infections and consider other factors including the nutrition, the toxic effects of HAART, age, and other causes. Risk of IRIS after initiation of HAART, which can exacerbate underlying infectious or inflammatory condition, should be a cause of concern. ^[26],[27]

Current research and future perspective

From the time when HIV individuals were started on therapy only when the CD4 counts fall below 200 cell/mm ³ , either due to cost or due to unavailability of drugs, time has changed now when HAART is freely available and at affordable costs. ^{[40],[41],[42],[43]} Now, the cause of concern is when to start antiretroviral therapy considering the toxic effects of antiretrovirals and the possibility of development drug resistance. Recent studies have demonstrated the importance of initiating antiretroviral therapy at a higher CD4 cell counts could reduce the risk of drug resistance. ^[40] HIV disease management of patients on HAART has been studied by many researchers with special emphasis on resource-poor countries. ^{[44],[45],[46]} Some studies have come out with guidelines and cost-effective diagnostic methods to achieve clinical benefit in financially constrained and conflict-striven countries. ^{[47],[48],[49]} Other studies have stressed on the need for availability of sufficient number of health-care providers in giving point of care to HIV-infected individuals. ^[50],[51] Until recently, the response to HAART therapy was mainly concentrated on CD4+T-cell counts and HIV/RNA viral load. In resource-poor countries, virological response is done based on laboratory indices like hemoglobin, total leucocyte count (TLC), and other easily done tests. ^{[32],[52],[53],[54],[55]} Previous studies have concentrated more on the treatment adherence, treatment failure, and drug resistance. Various studies have elaborated on the evaluation of predictors of death in HIV-infected individuals. ^[48] HIV patient care should be multifaceted involving specialist HIV primary care physicians, infectious disease specialists, and emergency physicians considering the ways by which HIV and HAART have changed treatment and management of HIV-infected individuals. We impress on the point that HIV by itself and in combination with HAART will be responsible for various disorders in infected patients, and physicians treating such patients need to consider patient evaluation based on all such factors before and after initiation of HAART to effectively reduce morbidity and mortality.

We express our gratitude to Dr. NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.115166