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The treatment of HIV infection has resulted in a remarkable reduction in mortality and improvement in the quality of life of infected individuals. The two specific goals of treatment are (1) to restore immunologic function by increasing the CD4 count, which reduces opportunistic infections and certain malignancies and (2) to reduce viral load, which reduces the chance of transmission to others. There is evidence that starting drug therapy as soon as possible after making the diagnosis of HIV infection is the best way to achieve these goals.
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Unfortunately, no drug regimen results in a “cure” (i.e., eradicates the virus from the body), but long-term suppression can be achieved. However, if drugs are stopped, the virus resumes active replication, and large amounts of infectious virus reappear.
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Transmission of HIV is significantly reduced by drug treatment because it lowers the amount of virus in the blood and other body fluids. Although drugs do not cure the infection, they can lower the amount of virus so that the frequency of transmission is very low. Adherence to drug treatment regimens is important both for the health of the infected patient as well as to protect uninfected individuals. When the viral load is undetectable, the likelihood of transmissions is very low leading to the expression “undetectable equals untransmittable.”
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Treatment of HIV infection typically involves multiple antiretroviral drugs. The use of a single drug (monotherapy) for treatment is not done because of the high rate of mutation to drug resistance.
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The choice of drugs is complex and depends on several factors (e.g., whether it is an initial infection or an established infection, the number of CD4 cells, the viral load, the resistance pattern of the virus, and whether the patient is pregnant or is coinfected with HBV or hepatitis C virus [HCV]). Table 45–3 describes the mechanism of action of the drugs and their main adverse effects. The number of drugs and the various determining factors mentioned previously make describing all the treatments beyond the scope of this book. The reader is advised to consult the Department of Health and Human Services Antiretroviral Therapy Guidelines or other reliable sources, such as the Medical Letter.
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The seven drug combinations recommended in 2019 for the treatment of newly infected adults are listed in Table 45–4. In brief, most of them consist of an integrase inhibitor plus two nucleoside reverse transcriptase inhibitors. Four of the five contain tenofovir alafenamide and emtricitabine. One regimen contains only two drugs, dolutegravir (integrase inhibitor) and lamivudine (nucleoside reverse transcriptase inhibitor). Another regimen containing only two drugs is dolutegravir (integrase inhibitor) and rilpivirine (non-nucleoside reverse transcriptase inhibitor).
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In January 2021, the FDA approved an injectable treatment consisting of a combination of cabotegravir and rilpivirine (Cabenuva). Two monthly doses are given, each drug is injected separately. The treatment suppressed HIV to undetectable levels for two years.
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These combinations are known as highly active antiretroviral therapy (HAART). HAART is very effective in prolonging life, improving quality of life, and reducing viral load but does not cure the chronic HIV infection (i.e., replication of HIV within CD4-positive cells continues indefinitely). Discontinuation of HAART almost always results in viremia (a return of the viral load to its pretreatment set point) and a fall in the CD4 count.
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Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
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Table 45–3 describes six nucleoside reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine) and a single nucleotide reverse transcriptase inhibitor (tenofovir). These drugs are characterized by not having a 3′ hydroxyl group on the ribose ring and therefore are chain-terminating drugs. They inhibit HIV replication by interfering with proviral DNA synthesis by reverse transcriptase. They cannot cure an infected cell of an already integrated copy of proviral DNA. Additional information on these “nucleoside analogue” drugs and the other antiretroviral drugs can be found in Chapter 35. Note that zalcitabine (Hivid), an NRTI analogue of cytosine, is no longer available.
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Two main problems limit the use of NTRIs: the emergence of resistance and adverse effects. The main adverse effects are described in Table 45–3. For example, the long-term use of zidovudine (ZDV) is limited by suppression of the bone marrow leading to anemia and neutropenia. This hematotoxicity is due to the inhibition of the mitochondrial DNA polymerase. Nevertheless, ZDV is used in postexposure prophylaxis (PEP) and to prevent vertical transmission from mother to fetus. Lamivudine and its analogue emtricitabine have the same mechanism of action as ZDV but are better tolerated, and one or another is a common component of HAART. Abacavir is also commonly used. Patients who have an HLA-B1701 allele are more likely to have a severe hypersensitivity reaction to abacavir. Patients should be tested for this gene before being prescribed abacavir.
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Nonnucleoside Reverse Transcriptase Inhibitors
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Table 45–3 describes five nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, etravirine, nevirapine, and rilpivirine) that are effective against HIV. Unlike the NRTIs, these drugs are not base analogues. Efavirenz (Sustiva) and nevirapine (Viramune) are the most commonly used drugs in this class. Efavirenz is a common component of HAART regimens, especially a single pill containing efavirenz, tenofovir, and emtricitabine (Atripla). Nevirapine is often used to prevent vertical transmission of HIV from mother to fetus. Both nevirapine and efavirenz can cause skin rashes and Stevens-Johnson syndrome. Rilpivirine is available as Odefsey, a fixed drug combination containing emtricitabine and tenofovir.
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Table 45–3 describes the currently available protease inhibitors (amprenavir atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, and a combination of lopinavir and ritonavir). Protease inhibitors, when combined with nucleoside analogues, are very effective in inhibiting viral replication and increasing CD4 cell counts and are commonly used in HAART regimens. Lopinavir and ritonavir are given in combination because ritonavir inhibits the degradation of lopinavir by cytochrome P450 enzymes, thereby increasing the concentration of lopinavir. A briefer way of saying that is ritonavir “boosts” lopinavir.
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Another drug that inhibits cytochrome P450 enzymes is cobicistat. It is particularly effective in enhancing the antiviral effect of elvitegravir, an integrase inhibitor. It is used in two four-drug, fixed-dose combinations marketed as Stribild and Genvoya. Both drugs contain elvitegravir, cobicistat, emtricitabine, and a tenofovir derivative. Cobicistat is also useful in enhancing the effect of protease inhibitors. The drug Prezcobix contains darunavir plus cobicistat and the drug Evotaz contains atazanavir and cobicistat.
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Mutants of HIV resistant to protease inhibitors can be a significant clinical problem. Resistance to one protease inhibitor often conveys resistance to all; however, the combination of two protease inhibitors, namely, ritonavir and lopinavir (Kaletra), is effective against both mutant and nonmutant strains of HIV. Also, darunavir is effective against many strains of HIV that are resistant to other protease inhibitors. Mutants of HIV resistant to both protease inhibitors and reverse transcriptase inhibitors have been recovered from patients.
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A major side effect of protease inhibitors is abnormal fat deposition in specific areas of the body, such as the back of the neck (Figure 45–7). The fat deposits in the back of the neck are said to give the person a “buffalo hump” appearance. These abnormal fat deposits are a type of lipodystrophy; the metabolic process by which this occurs is unknown. Saquinavir and indinavir are infrequently used because of toxicity and nelfinavir is no longer recommended.
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Treatment for acute HIV infection with two reverse transcriptase inhibitors and a protease inhibitor is often used. With this regimen, the viral load drops below the level of detection, CD4 cell counts rise, and CD8 activity increases. The long-term effect of this approach on rate of progression to AIDS has yet to be determined.
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Pregnant women infected with HIV should be treated with two nucleosides and a protease inhibitor. A typical regimen would include lamivudine, ZDV, and lopinavir/ritonavir. In addition, ZDV should be given to the neonate. These drugs appear not to damage the fetus, although rare instances of mitochondrial dysfunction and death attributed to ZDV have been reported. The reader is urged to consult the current information regarding the use of these drugs in pregnancy. A full discussion is beyond the scope of this book.
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Table 45–3 describes three entry inhibitors, enfuvirtide, maraviroc, and ibalizumab. Enfuvirtide (Fuzeon) is the first of a new class of anti-HIV drugs known as fusion inhibitors (i.e., they prevent the fusion of the viral envelope with the cell membrane). Enfuvirtide is a synthetic peptide that binds to gp41 on the viral envelope, thereby blocking the entry of HIV into the cell. It must be administered by injection and is quite expensive.
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Maraviroc (Selzentry) also prevents the entry of HIV into cells. It blocks the binding of the gp120 envelope protein of HIV to CCR-5, which is an important coreceptor on the cell surface. Before prescribing maraviroc, a laboratory test (Trofile assay) should be performed to ensure that the tropism of the patient’s strain of HIV is CCR5. Maraviroc should be used in combination with other antiretroviral drugs in patients infected with CCR5-tropic strains of HIV and in treatment-experienced adults infected with an HIV strain that is resistant to other antiretroviral drugs.
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Ibalizumab (Trogarzo) is a monoclonal antibody against CD4 protein that blocks entry of HIV. It is a “post-attachment” inhibitor, which means it blocks HIV from binding to CCR-5 or CXCR4 coreceptors after HIV has bound to the CD4 protein. It is approved for patients infected with multidrug resistant HIV.
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Raltegravir (Isentress) is the first drug to inhibit the HIV-encoded integrase (see Table 45–3). It is recommended for use in patients who have been treated with other antiretroviral drugs but continue to produce significant levels of HIV. Three additional integrase inhibitors are available: dolutegravir (Tivicay), elvitegravir (available as either Stribild or Genvoya in fixed combination with other drugs), and bictegravir (available as Biktarvy in fixed combination with emtricitabine and tenofovir). Dolutgravir is available in fixed combination with lamivudine (Dovato) and with rilpivirine (Juluca). The collective abbreviation INSTI is often used for these drugs. INSTI stands for INtegrase Strand Transfer Inhibitor.
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Cabotegravir is an injectable integrase inhibitor with a long-half life that is effective in preventing HIV infection for up to two months. The long-half-life is achieved by packaging the drug in nanoparticles. The structure of cabotegravir is similar to that of dolutegravir.
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Resistance to Antiretroviral Drugs
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Drug-resistant mutants of HIV have emerged that significantly affect the ability of both reverse transcriptase inhibitors and protease inhibitors to sustain their clinical efficacy. Approximately 10% of newly infected patients are infected with a strain of HIV resistant to at least one antiretroviral drug. Laboratory tests to detect mutant strains include both genotypic and phenotypic analysis. Genotyping reveals the presence of specific mutations in either the reverse transcriptase (RT) or protease (PR) genes. Phenotyping determines the ability of the virus to grow in cell culture in the presence of the drug. One method of phenotyping recovers the RT and PR genes from the patient’s virus and splices them into a test strain of HIV, which is then used to infect cells in culture. Another laboratory test can determine the tropism of the patient’s isolate (i.e., whether it uses CCR5 as its coreceptor). If so, then maraviroc can be used for treatment.
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Immune Reconstitution Inflammatory Syndrome
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Immune reconstitution inflammatory syndrome (IRIS) may occur in HIV-infected patients who are treated with a HAART regimen and who are coinfected with other microbes such as HBV, HCV, M. tuberculosis, M. avium complex, Cryptococcus neoformans, and Toxoplasma gondii. In this syndrome, an exacerbation of clinical symptoms occurs because the antiretroviral drugs enhance the ability to mount an inflammatory response. HIV-infected patients with a low CD4 count have a reduced capacity to produce inflammation, but HAART restores the inflammatory response, and as a result, symptoms become more pronounced. To avoid IRIS, the coinfection should be treated prior to instituting HAART whenever possible.