Human immunodeficiency virus (HIV) infection has become a health problem worldwide. Advances in treatment have made this disease not only manageable but have also dramatically decreased the incidence of opportunistic infections and decreased progression to acquired immunodeficiency syndrome (AIDS). Current guidelines on HIV treatment are more aggressive on when to start treatment, given that recent studies have shown improved outcomes with earlier initiation of therapy. In this review, we will focus on HIV antiretroviral therapy.
HIV is an enveloped ribonucleic retrovirus, subgroup lentivirus. There are two species of HIV that cause human disease. HIV-1 has high virulence and infectivity and is prevalent worldwide, HIV-2 has lower virulence and infectivity and is more prevalent in West Africa.
HIV prevalence has increased worldwide. This is related to an increased survival of HIV-infected individuals thanks to highly active antiretroviral therapy. The incidence of HIV has been declining and is expected to keep declining with increased awareness of the disease and the advent of pre-exposure prophylaxis therapy.
HIV transmission occurs through the exchange of bodily fluids. The most common route of transmission is sexual through the anogenital mucosa. It penetrates into the body by binding its GP120 molecule to CD4 molecules on dendritic cells in the mucosa. After entering the body, the virus invades macrophages (by binding GP120 to the chemokine receptor CCR5 as well as CD4) or T cell (by binding GP120 to the chemokine receptor CXCR4 as well as CD4) depending on the virus. After penetrating the cell, viral RNA will get transcribed to DNA by the virus own Reverse transcriptase. The DNA is then included into the host's DNA with the use of the virus Integrase enzyme. This DNA later transcribes into new RNA molecules that will be enveloped by proteins that have been cleaved into form by the HIV protease. These forms mature virions that later bud out of the cell and go to infect other cells. Highlighted in bold are those places where HIV antiretroviral therapy acts on different parts of the viral cycle.
Acute HIV infection may manifest as a mononucleosis-like syndrome with mainly nonspecific symptoms or be completely asymptomatic.
Chronic untreated infection progresses to CD-4 cell depletion and the development of acquired immunodeficiency syndrome with the appearance of different opportunistic infections and metabolic, cardiovascular, oncologic and neurocognitive comorbidities.
New more sensitive tests for HIV detection have been developed, and the diagnostic algorithm has been recently revised and updated. Initial diagnostic testing and screening should be done with antigen/antibody (4th gen) immunoassay that detects both HIV-1 and 2, as well as p24 antigen. This allows for earlier detection of infection by adding direct antigen testing to the initial screen (3rd generation immunoassays tested only for antibodies). A negative specimen does not require further testing. Patients with a positive test should be confirmed with an antibody immunoassay that differentiates HIV-1 from HIV-2 (as opposed to western blot). Positive tests define the diagnosis of HIV and subspecies. Patients that have a negative result or indeterminate in a confirmatory test should be tested with an HIV-1 NAT (nucleic acid testing). A positive test indicates acute HIV-1 infection. A negative test indicates a false positive result in initial testing and patient should be considered not infected. After confirmation of diagnosis and before initiation of treatment all patients should have a CD4 cell count, HIV RNA viral load, complete metabolic and blood count done, as well as genotypic resistance testing for the virus.
There are many different categories of HIV antiretroviral therapy:
Who and How to treat?
Based on recent multicenter-multinational randomized controlled trials the latest guidelines indicate that HIV antiretroviral therapy should be initiated early in the disease process regardless of CD4 cell count in all adult and adolescent patients. This strategy has been shown to decrease morbidity and mortality related to HIV infection as well as HIV transmission.
HIV antiretroviral therapy should always be done with combination regimens. Initial treatment usually consists of two NRTIs (usually abacavir/lamivudine or tenofovir/emtricitabine) in combination with a third antiviral drug from one of the following classes: integrase inhibitor, NNRTI or protease inhibitor plus an enhancer (cobicistat or ritonavir). This is based on the proven efficacy of this regimen and more favorable side effect profile. Alternative treatments may be considered in special patients.
Recommended initial regimens include four integrase inhibitor-based regimens (Dolutegravir/Tenofovir Fumarate/Emcitrabine; Raltegravir/Tenofovir Fumarate/Emcitrabine; Dolutegravir/abacavir/lamivudine (for HLA-B*5701 negative patients); Elitegravir-cobicistat/Tenofovir Fumarate/Emcitrabine, Elitegravir-cobicistat/Tenofovir Alafenamide/Emcitrabine) and one protease inhibitor-based regimen (Darunavir-ritonavir/Tenofovir Fumarate/Emcitrabine).
Listed integrase inhibitor-based regimens have high efficacy, safety, and tolerability, as well as low drug interactions for Raltegravir/Tenofovir Fumarate/Emtricitabine.
Although not as well tolerated, listed protease inhibitor regimen (Darunavir-ritonavir/Tenofovir Fumarate/Emcitrabine) is recommended for patients who are suspected will be relatively incompliant or patients with NRTI resistance, this is because of the high genetic barrier to resistance that protease inhibitors confer. Nevertheless, because it is somewhat lower efficacy, this regimen should be avoided in individuals with CD4 count less than 200 or HIV RNA greater than 100000).
Consideration should be taken to make treatment as comfortable as possible for the patient. Listed once a day regimens include Dolutegravir/abacavir/lamivudine and Elvitegravir-Cobicistat/Tenofovir Fumarate/Emtricitabine.
Other important considerations to take when starting HIV antiretroviral therapy:
Pre-exposure prophylaxis has been introduced in those groups who are at substantial risk of acquiring AIDS (e.g., MSM). It is an effective preventive tool for these groups, and it protects them from acquiring AIDS.
An evidence-based approach to preexposure HIV prophylaxis
More evidence has accumulated that pre-exposure HIV prophylaxis may be a better and more effective way to treat patients at high risk for HIV. Healthcare workers should be aware of this regimen since it is cheaper, simpler and safer than the traditional HAART regimen. Once preexposure prophylaxis is initiated, the goal is to ensure compliance, side effects of the medications and educate the patient on lowering of high-risk behaviors. While short-term studies indicate that pre-exposure HIV prophylaxis does work, more long-term studies are needed to determine if this also results in a lowering of HIV cases and slows down the HIV epidemic.