infectious diseases
Human Immunodeficiency Virus (HIV) Infection
Treatment of HIV Infection
Combinations of antiretroviral drugs (antiretroviral therapy [ART], sometimes called highly active ART [HAART] or combined ART [cART]) Prevention for opportunistic infections in patients at high risk (See also Antiretroviral Treatment of HIV Infection .) Treatment with ART is recommended for all patients, because disease-related complications can occur even in untreated patients with high CD4 counts and because the toxicity of antiretrovirals has decreased as new drugs have been developed. The benefits of ART outweigh the risks in every patient group and setting that has been carefully studied. In the Strategic Timing of AntiRetroviral Treatment (START) study, 5472 treatment-naïve patients with HIV infection and CD4 counts > 350 cells/mcL were randomized to start ART immediately (immediate initiation) or to defer ART until their CD4 count decreased to < 250 cells/mcL (deferred initiation). Risk of AIDS-related events (eg, tuberculosis, Kaposi sarcoma, malignant lymphomas) and non-AIDS–related events (eg, non-AIDS cancer, cardiovascular disease) was lower in the immediate-initiation group ( Treatment reference ). A few exceptional patients can control their HIV strain without treatment; they maintain normal CD4 counts and very low blood levels of HIV (long-term nonprogressors) or normal CD4 counts and undetectable blood levels of HIV (elite controllers). These patients may not require ART, but studies to determine whether treating them is helpful have not been done and would be difficult because there are few of these patients and they would likely do well not taking ART for long periods. ART aims to Reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL) Restore the CD4 count to a normal level (immune restoration or reconstitution) A poor CD4 count response is more likely if the CD4 count at initiation of treatment is low (especially if < 50/mcL) and/or the HIV RNA level is high. However, marked improvement is likely even in patients with advanced immunosuppression. An increased CD4 count correlates with markedly decreased risk of opportunistic infections, other complications, and death. With immune restoration, patients, even those with complications that have no specific treatment (eg, HIV-induced cognitive dysfunction) or that were previously considered untreatable (eg, progressive multifocal leukoencephalopathy), may improve. Outcomes are also improved for patients with cancers (eg, lymphoma, Kaposi sarcoma) and most opportunistic infections. Patients with most acute opportunistic infections benefit from early ART (initiated during the management of the opportunistic infection). However, for some opportunistic infections, such as tuberculous meningitis or cryptococcal meningitis, the evidence suggests that ART should be delayed (2 to 4 weeks in most cases) until the first phase of antimicrobial therapy for these infections is finished because of the increased frequency of adverse events and death. The goal of ART can usually be achieved if patients take their medications>95% of the time. However, maintaining this degree of adherence is difficult. Partial suppression (failure to lower plasma HIV RNA levels to undetectable levels) may select for single or multiple accumulated mutations in HIV that make viruses partially or completely resistant to a single drug or entire classes of drugs. Unless subsequent treatment uses drugs of other classes to which HIV remains sensitive, treatment is more likely to fail. The success of ART is assessed by measuring plasma HIV RNA levels every 8 to 12 weeks for the first 4 to 6 months or until HIV levels are undetectable and every 6 months thereafter. Increasing HIV levels are the earliest evidence of treatment failure and may precede a decreasing CD4 count by months. Maintaining patients on failing drug regimens selects for HIV mutants that are more drug-resistant. However, compared with wild-type HIV, these mutants appear less able to reduce the CD4 count, and failing drug regimens are often continued when no fully suppressive regimen can be found. If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant HIV strain to all available drugs. Genotypic and phenotypic assays are available and can help clinicians select a new regimen that should contain at least 2 and preferably 3 drugs to which the HIV strain is more susceptible. The dominant HIV strain in the blood of patients who are taken off antiretroviral therapy may revert over months to years to the wild-type (ie, susceptible) strain because the resistant mutants replicate more slowly and are replaced by the wild type. Thus, if patients have not been treated recently, the full extent of resistance may not be apparent through resistance testing, but when treatment resumes, strains with resistance mutations often reemerge from latency and again replace the wild-type HIV strain. Many patients living with HIV infection are taking complex regimens involving multiple pills to control the HIV RNA level (viral load), but often, no conventional HIV RNA resistance tests were done when viral treatment failed. With the availability of new co-formulated HIV drugs, many patients could benefit from simplification of their ART regimen, guided by HIV DNA archive genotype testing (GenoSure Archive). The HIV DNA genotype archive provides HIV-1 antiretroviral drug resistance data when conventional HIV RNA resistance testing cannot be done because patients have a low plasma HIV RNA level (< 500 copies/mL). The HIV DNA archive genotype test analyzes integrated and unintegrated archived HIV-1 proviral DNA embedded in host cells. The test amplifies cell-associated HIV-1 DNA from infected cells in whole blood samples, then uses next-generation sequencing technology to analyze the HIV-1 polymerase region. The positive predictive value of the HIV DNA archive resistance test results may enable clinicians to identify HIV-resistance mutations that were previously unidentified and to select a potentially simpler regimen with co-formulated drugs (≥ 2 drugs in a single pill). Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections. IRIS usually occurs in the first months of treatment but is occasionally delayed. IRIS can complicate virtually any opportunistic infection and even tumors (eg, Kaposi sarcoma) but is usually self-limited or responds to brief regimens of corticosteroids. IRIS has two forms: Paradoxical IRIS, which refers to worsening symptoms due to a previously diagnosed infection Unmasked IRIS, which refers to the first appearance of symptoms of an infection not previously diagnosed Paradoxical IRIStypically occurs during the first few months of treatment and usually resolves on its own. If it does not, corticosteroids, given for a short time, are often effective. Paradoxical IRIS is more likely to cause symptoms and symptoms are more likely to be severe when ART is started soon after treatment of an opportunistic infection is started. Thus, for some opportunistic infections, ART is delayed until treatment of the opportunistic infection has reduced or eliminated the infection. In patients withunmasked IRIS,the newly identified opportunistic infection is treated with antimicrobial drugs. Occasionally, when the symptoms are severe, corticosteroids are also used. Usually, when unmasked IRIS occurs, ART is continued. An exception is cryptococcal meningitis. Then ART is temporarily interrupted until the infection is controlled. Determining whether clinical deterioration is caused by treatment failure, IRIS, or both requires assessment of the persistence of active infections with cultures and can be difficult. Interruption of ART is usually safe if all drugs are stopped simultaneously, but levels of slowly metabolized drugs (eg,nevirapine) may remain high and thus increase the risk of resistance. Interruption may be necessary if intervening illnesses require treatment or if drug toxicity is intolerable or needs to be evaluated. After interruption to determine which drug is responsible for toxicity, clinicians can safely restart most drugs as monotherapy for up to a few days. NOTE: The most important exception isabacavir; patients who had fever or rash during previous exposure toabacavirmay develop severe, potentially fatal hypersensitivity reactions with reexposure. Risk of an adverse reaction toabacaviris 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing. Patients who had an adverse reaction toabacavirshould not be given the drug again. If they are reexposed to the drug, they may have a severe, potentially fatal hypersensitivity reaction. Risk of an adverse reaction toabacaviris 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing. (See also the United States Public Health Service and the HIV Medicine Association of the Infectious Diseases Society of America’sGuidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.) Effective chemoprophylaxis is available for many opportunistic infections and reduces rates of disease due toP. jirovecii,Candida,Cryptococcus, and MAC (Mycobacterium aviumcomplex). If therapy restores CD4 counts to above threshold values for>3 months, chemoprophylaxis can be stopped. Primary prophylaxisdepends on the CD4 count: (100 mg once/day). Patients with glucose-6-phosphate dehydrogenase ( Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency ) deficiency are at risk for developing severe hemolysis with CD4 count<50/mcL: Prophylaxis against disseminated MAC consists ofazithromycinorclarithromycin; if neither of these drugs is tolerated,rifabutincan be used.Azithromycincan be given weekly as two 600-mg tablets; it provides protection (70%) similar to dailyclarithromycinand does not interact with other drugs. If latent Tuberculosis (TB) is suspected (based on tuberculin skin tests, interferon-gamma release assays, high-risk exposure, personal history of active tuberculosis, or residence in a region with high tuberculosis prevalence), regardless of CD4 count, patients should be given For primary prophylaxis against some fungal infections (eg, esophageal candidiasis, cryptococcal meningitis or pneumonia), oralfluconazole100 to 200 mg once/day or 400 mg weekly is successful but is infrequently used because the cost per infection prevented is high and diagnosis and treatment of these infections are usually successful. Secondary prophylaxis(after control of the initial infection) is indicated if patients have had the following: Recurrent oral, vaginal, or esophageal Candidiasis ; Histoplasmosis : Latent Toxoplasmosis : This asymptomatic condition is indicated by serum antibodies (IgG) to Pneumocystis jirovecii Pneumonia None Herpes Simplex Virus (HSV) Infections None Aspergillosis (possibly) Detailed guidelines for prophylaxis of fungal (includingPneumocystis), viral, mycobacterial, and toxoplasmic infections are available atClinical Info: Federally Approved Clinical Practice Guidelines for HIV/AIDS. TheCDC 2022 recommendationsfor vaccination of HIV-infected patients aged ≥ 19 years include the following: Patients who have not received a conjugate Pneumococcal Vaccine or whose previous vaccination history is unknown should be given PCV15 or PCV20; if PCV15 is given, follow with PPSV23 ≥ 8 weeks after the PCV15 dose. All patients should be given the Influenza Vaccine annually. All patients should be given the Hepatitis B (HepB) Vaccine . Patients at risk of hepatitis A or desiring protection from it should be given the Hepatitis A (HepA) Vaccine . At the appropriate age, males and females should be given the Human Papillomavirus (HPV) Vaccine to prevent HPV-related cervical and anal cancers. Adults who have not been previously vaccinated with the Meningococcal Vaccine should be given a 2-dose primary series of MenACWY ≥ 8 weeks apart and revaccinate every 5 years. Patients who did not receive Diphtheria-Tetanus-Pertussis Vaccine (Tdap) as part of their completed All patients should be given the Herpes Zoster Vaccine . The Varicella Vaccine may be given to patients with CD4 percentage ≥ 15% and CD4 count ≥ 200/mcL, but the vaccine is contraindicated in patients with CD4 percentage < 15% or CD4 count < 200/mcL. Generally, inactivated vaccines should be used. These vaccines are effective less often in patients who are HIV-positive than in those who are HIV-negative. Because live-virus vaccines are potentially dangerous for patients with severe immunosuppression, expert opinion should be sought when dealing with patients at risk of primary varicella; recommendations vary (see vaccination information in Routine vaccinations and see table 1.INSIGHT START Study Group, Lundgren JD, Babiker AG, et al: Initiation of antiretroviral therapy in early asymptomatic HIV infection.N Engl J Med373 (9):795–807, 2015. doi: 10.1056/NEJMoa1506816 