InternalMed_Harrison

InternalMed_Harrison. Three main categories of lymphoma are seen in patients with HIV infection: grade III or IV immunoblastic lymphoma, Burkitt’s lymphoma, and primary CNS lymphoma. Approximately 90% of these lymphomas are B cell in phenotype; more than half contain EBV DNA. Some are associated with KSHV. These tumors may be either monoclonal or oligoclonal in nature and are probably in some way related to the pronounced polyclonal B cell activation seen in patients with AIDS.


InternalMed_Harrison

InternalMed_Harrison. Immunoblastic lymphomas account for ~60% of the cases of lymphoma in patients with AIDS. The majority of these are diffuse large B cell lymphomas (DLBCL). They are generally high grade and would have been classified as diffuse histiocytic lymphomas in earlier classification schemes. This tumor is more common in older patients, increasing in incidence from 0% in HIV-infected individuals <1 year old to >3% in those >50 years of age. Two variants of immunoblastic lymphoma that are seen primarily in HIV-infected patients are primary effusion lymphoma (PEL) and its solid variant, plasmacytic lymphoma of the oral cavity. PEL, also referred to as body cavity lymphoma, presents with lymphomatous pleural, pericardial, and/ or peritoneal effusions in the absence of discrete nodal or extranodal masses. The tumor cells do not express surface markers for B cells or T cells and are felt to represent a preplasmacytic stage of differentiation. While both HHV-8 and EBV DNA sequences have been found in


InternalMed_Harrison

InternalMed_Harrison. The tumor cells do not express surface markers for B cells or T cells and are felt to represent a preplasmacytic stage of differentiation. While both HHV-8 and EBV DNA sequences have been found in the genomes of the malignant cells from patients with body cavity lymphoma, KSHV is felt to be the driving force behind the oncogenesis (see above).


InternalMed_Harrison

InternalMed_Harrison. Small noncleaved cell lymphoma (Burkitt’s lymphoma) accounts for ~20% of the cases of lymphoma in patients with AIDS. It is most frequent in patients 10–19 years old and usually demonstrates characteristic c-myc translocations from chromosome 8 to chromosomes 14 or 22. Burkitt’s lymphoma is not commonly seen in the setting of immunodeficiency other than HIV-associated immunodeficiency, and the incidence of this particular tumor is more than 1000-fold higher in the setting of HIV infection than in the general population. In contrast to African Burkitt’s lymphoma, where 97% of the cases contain EBV genome, only 50% of HIV-associated Burkitt’s lymphomas are EBV-positive.


InternalMed_Harrison

InternalMed_Harrison. Primary CNS lymphoma accounts for ~20% of the cases of lymphoma in patients with HIV infection. In contrast to HIV-associated Burkitt’s lymphoma, primary CNS lymphomas are usually positive for EBV. In one study, the incidence of Epstein-Barr positivity was 100%. This malignancy does not have a predilection for any particular age group. The median CD4+ T cell count at the time of diagnosis is ~50/ μL. Thus, CNS lymphoma generally presents at a later stage of HIV infection than does systemic lymphoma. This may explain, at least in part, the poorer prognosis for this subset of patients.


InternalMed_Harrison

InternalMed_Harrison. The clinical presentation of lymphoma in patients with HIV infection is quite varied, ranging from focal seizures to rapidly growing mass lesions in the oral mucosa (Fig. 226-43) to persistent unexplained fever. At least 80% of patients present with extranodal disease, and a similar percentage have B-type symptoms of fever, night sweats, or weight loss. Virtually any site in the body may be involved. The most common extranodal site is the CNS, which is involved in approximately one-third of all patients with lymphoma. Approximately 60% of these cases are primary CNS lymphoma. Primary CNS lymphoma generally presents with focal neurologic deficits, including cranial nerve findings, headaches, and/or seizures. MRI or CT generally reveals a limited number (one to three) of 3to 5-cm lesions (Fig. 226-44). The lesions often show ring enhancement on contrast administration and may occur in any location. Contrast enhancement is usually less pronounced than that seen with toxoplasmosis.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 226-43 Immunoblastic lymphoma involving the hard palate of a patient with AIDS. Locations that are most commonly involved with CNS lymphoma are deep in the white matter. The main diseases in the differential diagnosis are cerebral toxoplasmosis and cerebral Chagas’ disease. In addition to the 20% of lymphomas in HIV-infected individuals that are primary CNS lymphomas, CNS disease is also seen in HIV-infected patients with systemic lymphoma. Approximately 20% of patients with systemic lymphoma have CNS disease in the form of leptomeningeal involvement. This fact underscores the importance of lumbar puncture in the staging evaluation of patients with systemic lymphoma.


InternalMed_Harrison

InternalMed_Harrison. Systemic lymphoma is seen at earlier stages of HIV infection than primary CNS lymphoma. In one series the mean CD4+ T cell count was 226/μL. In addition to lymph node involvement, systemic lymphoma may commonly involve the GI tract, bone marrow, liver, and lung. GI tract involvement is seen in ~25% of patients. Any site in the GI tract may be involved, and patients may complain of difficulty swallowing or abdominal pain. The diagnosis is usually suspected on the basis of CT or MRI of the abdomen. Bone marrow involvement is seen in ~20% of patients and may lead to pancytopenia. Liver and lung involvement are each seen in ~10% of patients. Pulmonary disease may present as a mass lesion, multiple nodules, or an interstitial infiltrate.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 226-44 Central nervous system lymphoma. Postcontrast T1-weighted MRI scan in a patient with AIDS, an altered mental status, and hemiparesis. Multiple enhancing lesions, some ring-enhancing, are present. The left sylvian lesion shows gyral and subcortical enhancement, and the lesions in the caudate and splenium (arrowheads) show enhancement of adjacent ependymal surfaces.


InternalMed_Harrison

InternalMed_Harrison. Both conventional and unconventional approaches have been 1271 employed in an attempt to treat HIV-related lymphomas. Systemic lymphoma is generally treated by the oncologist with combination chemotherapy. Earlier disappointing figures are being replaced with more optimistic results for the treatment of systemic lymphoma following the availability of more effective cART and the use of rituximab in CD20+ tumors. While there is some controversy regarding the use of antiretrovirals during chemotherapy, there is no question that their use overall in patients with HIV lymphoma has improved survival. Concerns regarding synergistic bone marrow toxicities with chemotherapy and cART are mitigated with the use of cART regimens that avoid bone marrow–toxic antiretrovirals. As in most situations in patients with HIV disease, those with higher CD4+ T cell counts tend to fare better. Response rates as high as 72% with a median survival of 33 months and disease-free intervals up to 9 years have been


InternalMed_Harrison

InternalMed_Harrison. with HIV disease, those with higher CD4+ T cell counts tend to fare better. Response rates as high as 72% with a median survival of 33 months and disease-free intervals up to 9 years have been reported. Treatment of primary CNS lymphoma remains a significant challenge. Treatment is complicated by the fact that this illness usually occurs in patients with advanced HIV disease. Palliative measures such as radiation therapy provide some relief. The prognosis remains poor in this group, with a 2-year survival of 29%.


InternalMed_Harrison

InternalMed_Harrison. Multicentric Castleman’s disease is a KSHV-associated lymphoproliferative disorder that is seen with an increased frequency in patients with HIV infection. While not a true malignancy, it shares many features with lymphoma including generalized lymphadenopathy, hepatosplenomegaly, and systemic symptoms of fever, fatigue, and weight loss. Pulmonary symptoms may be seen in ~50% of patients. KS is present in 75–82% of cases. Lymph node biopsies reveal a predomi nance of interfollicular plasma cells and/or germinal centers with vascularization and an “onionskin” (hyaline vascular) appearance. Prior to the availability of cART, HIV-infected patients with multicentric Castleman’s disease had a 15-fold increased risk of developing nonHodgkin’s lymphoma compared with HIV-infected patients in general. Treatment typically involves chemotherapy. Anecdotal reports of success with rituximab suggest that more specific treatment may be successful, although, in one series treatment with rituximab was


InternalMed_Harrison

InternalMed_Harrison. Treatment typically involves chemotherapy. Anecdotal reports of success with rituximab suggest that more specific treatment may be successful, although, in one series treatment with rituximab was associated with worsening of coexisting KS. The median survival of patients with treated multicentric Castleman’s disease pre-cART was initially reported as 14 months. This has increased to a 2-year survival of more than 90% in the era of cART.


InternalMed_Harrison

InternalMed_Harrison. Evidence of infection with human papillomavirus (HPV), associated with intraepithelial dysplasia of the cervix or anus, is approximately twice as common in HIV-infected individuals as in the general population and can lead to intraepithelial neoplasia and eventually invasive cancer. In a series of studies, HIV-infected men were examined for evidence of anal dysplasia, and Papanicolaou (Pap) smears were found to be abnormal in 20–80%. These changes tend to persist and are generally not affected by cART, raising the possibility of a subsequent transition to a more malignant condition. While the incidence of an abnormal Pap smear of the cervix is ~5% in otherwise healthy women, the incidence of abnormal cervical smears in women with HIV infection is 30–60%, and invasive cervical cancer is included as an AIDS-defining condition. While only small increases in the absolute numbers of cervical or anal cancers have been seen as a consequence of HIV infection, the relative risk of these


InternalMed_Harrison

InternalMed_Harrison. is included as an AIDS-defining condition. While only small increases in the absolute numbers of cervical or anal cancers have been seen as a consequence of HIV infection, the relative risk of these conditions when one compares HIV-infected to -noninfected men and women is on the order of 10to 100-fold. Given the high rates of dysplasia and relative risks for cervical and anal cancer, a comprehensive gynecologic and rectal examination, including Pap smear, is indicated at the initial evaluation and 6 months later for all patients with HIV infection. If these examinations are negative at both time points, the patient should be followed with yearly evaluations. If an initial or repeat Pap smear shows evidence of severe inflammation with reactive squamous changes, the next Pap smear should be performed at 3 months. If, at any time, a Pap smear shows evidence of squamous intraepithelial lesions, colposcopic examination with biopsies as indicated should be performed. The 2-year survival


InternalMed_Harrison

InternalMed_Harrison. be performed at 3 months. If, at any time, a Pap smear shows evidence of squamous intraepithelial lesions, colposcopic examination with biopsies as indicated should be performed. The 2-year survival rate for HIV-infected patients with invasive cervical cancer is 64% compared with 79% in non-HIV-infected patients. In addition to rectal and cervical lesions, HPV can also lead to head and


InternalMed_Harrison

InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1272 neck cancers. In one study of men who have sex with men, 25% were found to have oral HPV; high-risk HPV genotypes were three times more common in the HIV-infected men. The most common HPV genotypes in the general population and the genotypes upon which current HPV vaccines are based are 6, 11, 16, and 18. This is not the case in the HIV-infected population, where other genotypes such as 58 and 53 also are prominent. This raises concerns about the level of effectiveness of the current HPV vaccines for HIV-infected patients. Despite this, it is recommended that patients with HIV infection be vaccinated against HPV.


InternalMed_Harrison

InternalMed_Harrison. A syndrome was recognized in 1992 characterized by an absolute CD4+ T cell count of <300/μL or <20% of total T cells on a minimum of two occasions at least 6 weeks apart; no evidence of HIV-1, HIV-2, HTLV-1, or HTLV-2 on testing; and the absence of any defined immunodeficiency or therapy associated with decreased levels of CD4+ T cells. By mid-1993, ~100 patients had been described. After extensive multicenter investigations, a series of reports were published in early 1993, which together allowed a number of conclusions. Idiopathic CD4+ lymphocytopenia (ICL) is a very rare syndrome, as determined by studies of blood donors and cohorts of HIV-seronegative men who have sex with men. Cases were clearly identified as early as 1983 and were remarkably similar to the clinical features of ICL that had been identified decades earlier. The definition of ICL based on CD4+ T cell counts coincided with the ready availability of testing for CD4+ T cells in patients suspected of being


InternalMed_Harrison

InternalMed_Harrison. of ICL that had been identified decades earlier. The definition of ICL based on CD4+ T cell counts coincided with the ready availability of testing for CD4+ T cells in patients suspected of being immunodeficient. Although, as a result of immune deficiency, certain patients with ICL develop some of the opportunistic diseases (particularly cryptococcosis, nontuberculous mycobacterial infections, and cervical dysplasia) seen in HIV-infected patients, the syndrome is demographically, clinically, and immunologically unlike HIV infection and AIDS. Fewer than half of the reported ICL patients had risk factors for HIV infection, and there were wide geographic and age distributions. The fact that a significant proportion of patients did have risk factors probably reflects a selection bias, in that physicians who take care of HIV-infected patients are more likely to monitor CD4+ T cells. Approximately half of the patients are women, compared with approximately one-third among HIV-infected


InternalMed_Harrison

InternalMed_Harrison. that physicians who take care of HIV-infected patients are more likely to monitor CD4+ T cells. Approximately half of the patients are women, compared with approximately one-third among HIV-infected individuals in the United States. Many patients with ICL remained clinically stable, and their condition did not deteriorate progressively as is common with seriously immunodeficient HIV-infected patients. Approximately 15% of patients with ICL experience spontaneous reversal of the CD4+ T lymphocytopenia. Immunologic abnormalities in ICL are somewhat different from those of HIV infection. ICL patients often have increases in CD4+ T cell activation with decreases in CD8+ T cells and B cells. Furthermore, immunoglobulin levels are either normal or, more commonly, decreased in patients with ICL, compared with the usual hypergammaglobulinemia of HIV-infected individuals. Virologic studies of these patients have revealed no evidence of HIV-1, HIV2, HTLV-1, or HTLV-2 or of any other mononuclear


InternalMed_Harrison

InternalMed_Harrison. compared with the usual hypergammaglobulinemia of HIV-infected individuals. Virologic studies of these patients have revealed no evidence of HIV-1, HIV2, HTLV-1, or HTLV-2 or of any other mononuclear cell–tropic virus. Furthermore, there has been no epidemiologic evidence to suggest that a transmissible microbe was involved. The cases of ICL have been widely dispersed, with no clustering. Close contacts and sexual partners who were studied were clinically well and were serologically, immunologically, and virologically negative for HIV. ICL is a heterogeneous syndrome, and it is highly likely that there is no common cause; however, there may be common causes among subgroups of patients that are currently unrecognized.


InternalMed_Harrison

InternalMed_Harrison. Patients who present with laboratory data consistent with ICL should be worked up for underlying diseases that could be responsible for the immune deficiency. If no underlying cause is detected, no specific therapy should be initiated. However, if opportunistic diseases occur, they should be treated appropriately (see above). Depending on the level of the CD4+ T cell count, patients should receive prophylaxis for the commonly encountered opportunistic infections.


InternalMed_Harrison

InternalMed_Harrison. The CDC guidelines call for the testing for HIV infection to be a part of routine medical care. It is recommended that the patient be informed of the intention to test, as is the case with other routine laboratory determinations, and be given the opportunity to “opt out.” Such an approach is critical to the goal of identifying as many infected individuals as possible since 16–18% of the >1.1 million individuals in the United States who are HIV-infected are not aware of their status. Under these circumstances of routine testing, although it is desirable, pretest counseling may not always be built into the testing process. However, no matter how well prepared a patient is for adversity, the discovery of a diagnosis of HIV infection is a devastating event. Thus, physicians should be sensitive to this fact and, where possible, execute some degree of pretest counseling to at least partially prepare the patient should the results demonstrate the presence of HIV infection. Following a


InternalMed_Harrison

InternalMed_Harrison. to this fact and, where possible, execute some degree of pretest counseling to at least partially prepare the patient should the results demonstrate the presence of HIV infection. Following a diagnosis of HIV infection, the health care provider should be prepared to immediately activate support systems for the newly diagnosed patient. These should include an experienced social worker or nurse who can spend time talking to the person and ensuring that he or she is emotionally stable. Most communities have HIV support centers that can be of great help in these difficult situations.


InternalMed_Harrison

InternalMed_Harrison. The treatment of patients with HIV infection requires not only a comprehensive knowledge of the possible disease processes that may occur and up-to-date knowledge of and experience with cART, but also the ability to deal with the problems of a chronic, potentially life-threatening illness. A comprehensive knowledge of internal medicine is required to deal with the changing spectrum of illnesses associated with HIV infection, many of which are similar to a state of accelerated aging. Great advances have been made in the treatment of patients with HIV infection. The appropriate use of potent cART and other treatment and prophylactic interventions are of critical importance in providing each patient with the best opportunity to live a long and healthy life despite the presence of HIV infection. In contrast to the earlier days of this epidemic, a diagnosis of HIV infection need no longer be equated with having an inevitably fatal disease. In addition to medical interventions, the health


InternalMed_Harrison

InternalMed_Harrison. In contrast to the earlier days of this epidemic, a diagnosis of HIV infection need no longer be equated with having an inevitably fatal disease. In addition to medical interventions, the health care provider has a responsibility to provide each patient with appropriate counseling and education concerning their disease as part of a comprehensive care plan. Patients must be educated about the potential transmissibility of their infection and about the fact that while health care providers may refer to levels of the virus as “undetectable,” this is more a reflection of the sensitivity of the assay being used to measure the virus than a comment on the presence or absence of the virus. It is important for patients to be aware that the virus is still present and capable of being transmitted at all stages of HIV disease. Thus, there must be frank discussions concerning sexual practices and the sharing of syringes and other paraphernalia used in illicit drug use. The treating physician not


InternalMed_Harrison

InternalMed_Harrison. all stages of HIV disease. Thus, there must be frank discussions concerning sexual practices and the sharing of syringes and other paraphernalia used in illicit drug use. The treating physician not only must be aware of the latest medications available for patients with HIV infection but also must educate patients concerning the natural history of their illness and listen and be sensitive to their fears and concerns. As with other diseases, therapeutic decisions should be made in consultation with the patient, when possible, and with the patient’s proxy if the patient is incapable of making decisions. In this regard, it is recommended that all patients with HIV infection, and in particular those with CD4+ T cell counts <200/μL, designate a trusted individual with durable power of attorney to make medical decisions on their behalf, if necessary.


InternalMed_Harrison

InternalMed_Harrison. Following a diagnosis of HIV infection, there are several examinations and laboratory studies that should be performed to help determine the extent of disease and provide baseline standards for future reference (Table 226-19). In addition to routine chemistry, fasting lipid profile, aspartate aminotransferase, alanine aminotransferase, total and direct bilirubin, fasting glucose and hematology screening panels, Pap smear, urinalysis, and chest x-ray, one should also obtain a CD4+ T cell count, two separate plasma HIV


InternalMed_Harrison

InternalMed_Harrison. History and physical examination Routine chemistry and hematology AST, ALT, direct and indirect bilirubin Lipid profile and fasting glucose CD4+ T lymphocyte count Two plasma HIV RNA levels HIV resistance testing HLA-B5701 screening RPR or VDRL test Anti-Toxoplasma antibody titer PPD skin test or IFN-γ release assay Mini-Mental Status Examination Serologies for hepatitis A, hepatitis B, and hepatitis C Immunization with pneumococcal polysaccharide; influenza as indicated Immunization with hepatitis A and hepatitis B if seronegative Counseling regarding natural history and transmission Help contacting others who might be infected Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; PPD, purified protein derivative; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.


InternalMed_Harrison

InternalMed_Harrison. RNA levels, an HIV resistance test, a rapid plasma reagin or VDRL test, an anti-Toxoplasma antibody titer, and serologies for hepatitis A, B, and C. A PPD test or IFN-γ release assay should be done and an MMSE performed and recorded. A pregnancy test should be done in women in whom the drug efavirenz is being considered, and HLA-B5701 testing should be done in all patients in whom the drug abacavir is being considered. Patients should be immunized with pneumococcal polysaccharide, with annual influenza shots, and, if seronegative for these viruses, with HPV, hepatitis A, and hepatitis B vaccines. The status of hepatitis C infection should be determined. In addition, patients should be counseled with regard to sexual practices and needle sharing, and counseling should be offered to those whom the patient knows or suspects may also be infected. Once these baseline activities are performed, shortand long-term medical management strategies should be developed based on the most recent


InternalMed_Harrison

InternalMed_Harrison. whom the patient knows or suspects may also be infected. Once these baseline activities are performed, shortand long-term medical management strategies should be developed based on the most recent information available and modified as new information becomes available. The field of HIV medicine is changing rapidly, and it is difficult to remain fully up to date. Fortunately there are a series of excellent sites on the Internet that are frequently updated, and they provide the most recent information on a variety of topics, including consensus panel reports on treatment (Table 226-20).


InternalMed_Harrison

InternalMed_Harrison. Combination antiretroviral therapy (cART), also referred to as highly active antiretroviral therapy (HAART), is the cornerstone of management of patients with HIV infection. Following the initiation of widespread use of cART in the United States in 1995–1996, marked declines were noted in the incidence of most AIDS-defining conditions (Fig. 226-33). Suppression of HIV replication is an important component in prolonging life as well as in improving the quality of life in patients with HIV infection. Adequate suppression requires www.aidsinfo.nih.gov AIDSinfo, a service of the U.S. Department of Health and Human Services, posts federally approved treatment guidelines for HIV and AIDS; provides information on federally funded and privately funded clinical trials and CDC publications and data www.cdcnpin.org Updates on epidemiologic data and prevention information from the CDC Abbreviation: CDC, Centers for Disease Control and Prevention.


InternalMed_Harrison

InternalMed_Harrison. strict adherence to prescribed regimens of antiretroviral drugs. This 1273 has been facilitated by the coformulations of antiretrovirals and the development of once-daily regimens. Unfortunately, many of the most important questions related to the treatment of HIV disease currently lack definitive answers. Among them are the questions of when therapy should be started, what the best initial regimen is, when a given regimen should be changed, and what it should be changed to when a change is made. Notwithstanding these uncertainties, the physician and patient must come to a mutually agreeable plan based on the best available data. In an effort to facilitate this process, the U.S. Department of Health and Human Services makes available on the Internet (www.aidsinfo.nih.gov) a series of periodically updated guidelines, including “Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents” and “Guidelines for the Prevention of Opportunistic Infections in


InternalMed_Harrison

InternalMed_Harrison. periodically updated guidelines, including “Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents” and “Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus.” At present, an extensive clinical trials network, involving both clinical investigators and patient advocates, is in place attempting to develop improved approaches to therapy. Consortia comprising representatives of academia, industry, independent foundations, and the federal government are involved in the process of drug development, including a wide-ranging series of clinical trials. As a result, new therapies and new therapeutic strategies are continually emerging. New drugs are often available through expanded-access programs prior to official licensure. Given the complexity of this field, decisions regarding cART are best made in consultation with experts.


InternalMed_Harrison

InternalMed_Harrison. Currently available drugs for the treatment of HIV infection as part of a combination regimen fall into four categories: those that inhibit the viral reverse transcriptase enzyme (nucleoside and nucleotide reverse transcriptase inhibitors; nonnucleoside reverse transcriptase inhibitors), those that inhibit the viral protease enzyme (protease inhibitors), those that inhibit the viral integrase enzyme (integrase inhibitors), and those that interfere with viral entry (fusion inhibitors; CCR5 antagonists) (Table 226-21; Fig. 226-45).


InternalMed_Harrison

InternalMed_Harrison. The FDA-approved reverse transcriptase inhibitors include the nucleoside analogues zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, and emtricitabine; the nucleotide analogue tenofovir; and the nonnucleoside reverse transcriptase inhibitors nevirapine, delavirdine, efavirenz, and etravirine (Table 226-21; Fig. 226-45). These represent the first class of drugs licensed for the treatment of HIV infection. They are indicated for this use as part of combination regimens. It should be stressed that none of these drugs should be used as monotherapy for HIV infection due to the relative ease with which drug resistance may develop under such circumstances. Thus, when lamivudine, emtricitabine, or tenofovir is used to treat hepatitis B infection in the setting of HIV infection, one should ensure that the patient is also on additional antiretroviral medication. The reverse transcriptase inhibitors block the HIV replication cycle at the point of RNA-dependent DNA synthesis,


InternalMed_Harrison

InternalMed_Harrison. one should ensure that the patient is also on additional antiretroviral medication. The reverse transcriptase inhibitors block the HIV replication cycle at the point of RNA-dependent DNA synthesis, the reverse transcription step. While the nonnucleoside reverse transcriptase inhibitors are quite selective for the HIV-1 reverse transcriptase, the nucleoside and nucleotide analogues inhibit a variety of DNA polymerases in addition to those of the HIV-1 reverse transcriptase. For this reason, serious side effects are more varied with the nucleoside analogues and include mitochondrial damage that can lead to hepatic steatosis and lactic acidosis as well as peripheral neuropathy and pancreatitis. The use of either of the thymidine analogues zidovudine and stavudine has been associated with a syndrome of hyperlipidemia, glucose intolerance/insulin resistance, and fat redistribution often referred to as lipodystrophy syndrome (discussed in “Diseases of the Endocrine System and Metabolic


InternalMed_Harrison

InternalMed_Harrison. a syndrome of hyperlipidemia, glucose intolerance/insulin resistance, and fat redistribution often referred to as lipodystrophy syndrome (discussed in “Diseases of the Endocrine System and Metabolic Disorders,” above). The reverse transcriptase inhibitors preferred for use according to the DHHS Panel on the use of antiretroviral drugs are lamivudine, emtricitabine, abacavir, tenofovir, and rilpivirine.


InternalMed_Harrison

InternalMed_Harrison. Lamivudine (3TC; 2’,3’-dideoxy-3’-thiacytidine) is the fifth of the nucleoside analogues to be licensed in the United States. It is the negative enantiomer of a dideoxy analogue of cytidine. In actual practice, lamivudine or the closely related drug emtricitabine (see Human Immunodeficiency Virus Disease: AIDS and Related Disorders Etravirine (Intelence) Licensed In combination with other antiretroviral agents in treatment-experienced patients whose HIV is resistant to nonnucleoside reverse transcriptase inhibitors and other antiretroviral medications but the discontinuation rate in the indinavir group was unexpectedly high, accounting for most treatment “failures”); CD4 cell increase (~140/μL in each group) at 24 weeks 200 mg bid Higher rates of HIV RNA suppression to <50 copies/mL (56% vs 39%); greater increases in CD4+ T cell count (89 vs 64 cells) compared to placebo when given in combination with an optimized background regimen Rash, nausea, hypersensitivity reactions


InternalMed_Harrison

InternalMed_Harrison. Enfuvirtide (Fuzeon) Licensed In combination 90 mg SC bid In treatment of experienced with other agents in patients, superior to placebo when treatment-experienced added to new optimized back-patients with evidence ground (37% vs 16% with <400 HIV of HIV-1 replication Maraviroc (Selzentry) Licensed In combination with 150–600 mg bid At 24 weeks, among 635 patients other antiretroviral depending on con-with CCR5-tropic virus and HIV-1 agents in adults infected comitant medica-RNA >5000 copies/mL despite at with only CCR5-tropic tions (see text) least 6 months of prior therapy HIV-1 with at least 1 agent from 3 of the 4 antiretroviral drug classes, 61% of patients randomized to maraviroc achieved HIV RNA levels <400 copies/mL compared with 28% of patients randomized to placebo Local injection reactions, hypersensitivity reactions, increased rate of bacterial pneumonia Hepatotoxicity, nasopharyngitis, fever, cough, rash, abdominal pain, dizziness, musculoskeletal symptoms


InternalMed_Harrison

InternalMed_Harrison. Local injection reactions, hypersensitivity reactions, increased rate of bacterial pneumonia Hepatotoxicity, nasopharyngitis, fever, cough, rash, abdominal pain, dizziness, musculoskeletal symptoms Human Immunodeficiency Virus Disease: AIDS and Related Disorders Raltegravir (Isentress) Licensed In combination with 400 mg bid other antiretroviral agents (Available only in combination with cobicistat, tenofovir, and emtricitabine [Stribild]) Dolutegravir Licensed In combination with 50 mg daily for (Tivicay) 50 mg twice daily for treatment-experienced patients or those also receiving efavirenz or rifampin At 24 weeks, among 436 patients with 3-class drug resistance, 76% of patients randomized to receive raltegravir achieved HIV RNA levels <400 copies/mL compared with 41% of patients randomized to receive placebo Noninferior to raltegravir or atazanavir/ritonavir in treatment-experienced patients.


InternalMed_Harrison

InternalMed_Harrison. Noninferior to raltegravir or atazanavir/ritonavir in treatment-experienced patients. Noninferior to raltegravir, superior to efavirenz or darunavir/ritonavir Nausea, headache, diarrhea, CPK elevation, muscle weakness, rhabdomyolysis Diarrhea, nausea, upper respiratory infections, headache Insomnia, headache, hypersensitivity reactions, hepatotoxicity Abbreviations: ARC, AIDS-related complex; NRTIs, nonnucleoside reverse transcriptase inhibitors.


InternalMed_Harrison

InternalMed_Harrison. Insomnia, headache, hypersensitivity reactions, hepatotoxicity Abbreviations: ARC, AIDS-related complex; NRTIs, nonnucleoside reverse transcriptase inhibitors. 1276 below) is a frequent element of many different combination regi-on hepatitis B, direct effects on HIV, and immune reconstitution mens currently in use. These two drugs and the nucleotide reverse (see above). To prevent the development of resistant strains of HIV, transcriptase inhibitor tenofovir (see below) also have activity these drugs should never be used on their own for the treatment against hepatitis B virus. For this reason flares of hepatitis may be of hepatitis B in the patient with HIV infection. Lamivudine is avail-seen in co-infected patients starting and/or or stopping any of able either alone or in coformulations including zidovudine and/or these three agents due to the confounding issues of direct effects abacavir (Table 226-22). One reason behind the excellent synergy


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 226-45 Molecular structures of antiretroviral agents. Human Immunodeficiency Virus Disease: AIDS and Related Disorders seen between lamivudine and the other nucleoside analogues may be that strains of HIV resistant to lamivudine (M184V substitution) appear to have enhanced sensitivity to other nucleosides, and thus development of dual resistance is more difficult. In addition, there is a suggestion that 3TC-resistant strains of HIV may be less virulent and are less able to generate new mutants than are strains of HIV that are 3TC-sensitive. Lamivudine is among the best tolerated and least toxic of the nucleoside analogues. aNot licensed in the United States.


InternalMed_Harrison

InternalMed_Harrison. aNot licensed in the United States. Emtricitabine (FTC; 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3oxathiolan-5-yl]cytosine) is the negative enantiomer of a thio analogue of cytidine with a fluorine in the 5 position. It is licensed for use in combination with other antiretroviral agents for treatment of HIV-1 infection in adults. Compared with lamivudine, it is similar in activity and has a longer half-life. It is available either alone or coformulated with tenofovir or tenofovir and efavirenz (Table 226-22). As with lamivudine, resistance to emtricitabine is associated with the M184V mutation in reverse transcriptase. Viruses showing the K65R mutation in reverse transcriptase may have reduced susceptibility to emtricitabine.


InternalMed_Harrison

InternalMed_Harrison. Abacavir {(1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin9-yl]-2-cyclopentene-1-methanol sulfate (salt)(2:1)} is a synthetic carbocyclic analogue of the nucleoside guanosine. It is licensed to be used in combination with other antiretroviral agents for the treatment of HIV-1 infection. Hypersensitivity reactions that may occur with initial therapy or rechallenge have been reported in ~4% of patients treated with this drug, and patients developing signs or symptoms of hypersensitivity such as fever, skin rash, fatigue, and GI symptoms should discontinue the drug and not restart it. Fatal hypersensitivity reactions have been reported with rechallenge. Abacavir hypersensitivity occurs with a higher frequency in patients who are HLA-B5701-positive. It is recommended that patients be screened for HLA-B5701 prior to initiation of abacavir and that 1278 abacavir only be used as a last resort and with close monitoring in patients who are HLA-B5701-positive. Abacavir-resistant strains of HIV


InternalMed_Harrison

InternalMed_Harrison. for HLA-B5701 prior to initiation of abacavir and that 1278 abacavir only be used as a last resort and with close monitoring in patients who are HLA-B5701-positive. Abacavir-resistant strains of HIV are typically also resistant to lamivudine, emtricitabine, didanosine, and zalcitabine. In randomized trials abacavir was found to be inferior to tenofovir in patients with baseline HIV RNA levels >100,000 copies/mL. Abacavir is formulated alone as well as in combination with lamivudine, with zidovudine and lamivudine or with lamivudine and dolutegravir. Tenofovir disoproxil fumarate (9-[(R)-2-[[bis[[(isopropoxycarbonyl) oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate [1:1]) is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. It undergoes diester hydrolysis to form the nucleoside monophosphate (nucleotide) tenofovir and is the first nucleotide analogue to be licensed for treatment of HIV infection. It is indicated in combination with other


InternalMed_Harrison

InternalMed_Harrison. hydrolysis to form the nucleoside monophosphate (nucleotide) tenofovir and is the first nucleotide analogue to be licensed for treatment of HIV infection. It is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection and in combination with emtricitabine for pre-exposure prophylaxis for HIV-1 prevention in populations at high risk of HIV infection. HIV isolates with increased resistance typically express a K65R mutation in reverse transcriptase and a threeto fourfold reduction in sensitivity to tenofovir. Tenofovir is primarily eliminated by the kidneys, and renal impairment including a Fanconi-like syndrome with hypophosphatemia may occur. Tenofovir is contraindicated in patients with renal impairment. An investigational prodrug analogue with less renal toxicity, tenofovir alafenamide fumarate is currently in clinical trials. Small but statistically significant decreases in bone mineral density have been noted in patients receiving tenofovir.


InternalMed_Harrison

InternalMed_Harrison. renal toxicity, tenofovir alafenamide fumarate is currently in clinical trials. Small but statistically significant decreases in bone mineral density have been noted in patients receiving tenofovir. Coadministration of tenofovir with didanosine leads to a 60% increase in didanosine levels, and thus doses of didanosine need to be adjusted and patients monitored carefully if these two drugs are used in combination. In addition, CD4+ T cell increases may be blunted in patients on this combination. Coadministration of tenofovir with atazanavir leads to a decrease in atazanavir levels, and thus low-dose ritonavir (see below) needs to be added when these drugs are used in combination. Tenofovir is available alone and coformulated with emtricitabine, emtricitabine and efavirenz, emtricitabine and rilpivirine, or emtricitabine, elvitegravir and cobicistat. Nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine are nonnucleoside inhibitors of the HIV-1 reverse transcriptase and are


InternalMed_Harrison

InternalMed_Harrison. and rilpivirine, or emtricitabine, elvitegravir and cobicistat. Nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine are nonnucleoside inhibitors of the HIV-1 reverse transcriptase and are licensed for use in combination with nucleoside analogues for the treatment of HIV-infected adults. Coformulations that include efavirenz or nevirapine are available (Table 226-22). These agents inhibit reverse transcriptase by binding to regions of the enzyme outside the active site and causing conformational changes in the enzyme that render it inactive. Although these agents are active in the nanomolar range, they are also very selective for the reverse transcriptase of HIV-1, have no activity against HIV-2, and, when used as mono-therapy, are associated with the rapid emergence of drug-resistant mutants (Table 226-21; Fig. 226-46). Efavirenz and rilpivirine are administered once a day, nevirapine and etravirine twice a day, and delavirdine three times a day. All are associated with


InternalMed_Harrison

InternalMed_Harrison. mutants (Table 226-21; Fig. 226-46). Efavirenz and rilpivirine are administered once a day, nevirapine and etravirine twice a day, and delavirdine three times a day. All are associated with the development of a maculopapular rash, generally seen within the first few weeks of therapy. While it is possible to treat through this rash, it is important to be sure that one is not dealing with a more severe eruption such as Stevens-Johnson syndrome by looking carefully for signs of mucosal involvement, significant fever, or painful lesions with desquamation. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, have been reported in patients treated with nevirapine. There is a suggestion that this is more common in women with higher CD4+ T cell counts. Many patients treated with efavirenz note a feeling of light-headedness, dizziness, or out of sorts following the initiation of therapy. Some


InternalMed_Harrison

InternalMed_Harrison. is more common in women with higher CD4+ T cell counts. Many patients treated with efavirenz note a feeling of light-headedness, dizziness, or out of sorts following the initiation of therapy. Some complain of vivid dreams. These symptoms tend to disappear after several weeks of therapy. Aside from difficulties with dreams, taking efavirenz at bedtime may minimize the side effects. Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Women of childbearing potential should undergo pregnancy testing prior to initiation of efavirenz. Efavirenz is commonly used in combination with two nucleoside analogues as part of initial treatment regimens. Etravirine is a diarylpyrimidine derivative currently licensed for treatment of HIV infection in combination with other agents. In contrast to the other nonnucleoside reverse transcriptase inhibitors, which all exhibit cross-resistance, etravirine may be active against strains of HIV that are resistant to


InternalMed_Harrison

InternalMed_Harrison. with other agents. In contrast to the other nonnucleoside reverse transcriptase inhibitors, which all exhibit cross-resistance, etravirine may be active against strains of HIV that are resistant to other nonnucleoside reverse transcriptase inhibitors. Among its side effects are rash, headache, nausea, and diarrhea. Rilpivirine is effective across a broad range of NNRTI-resistant viruses and shares cross-resistance with etravirine. It is better tolerated and a has higher rate of virologic failure than efavirenz, particularly in those with HIV RNA >100,000. It is only available as part of a combination regimen with tenofovir and emtricitabine.


InternalMed_Harrison

InternalMed_Harrison. The HIV-1 protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, lopinavir/ritonavir, atazanavir, tipranavir, and darunavir) are a major part of the therapeutic armamentarium of antiretrovirals. When used as part of initial regimens in combination with reverse transcriptase inhibitors, these agents have been shown to be capable of suppressing levels of HIV replication to under 50 copies/mL in the majority of patients for a minimum of 5 years. As in the case of reverse transcriptase inhibitors, resistance to protease inhibitors can develop rapidly in the setting of monotherapy, and thus these agents should be used only as part of combination therapeutic regimens. A summary of known resistance mutations for protease inhibitors is shown in Fig. 226-46. The protease inhibitors preferred for use according to the DHHS Panel on the use of antiretroviral drugs are ritonavir (only as a pharmacokinetic enhancer), atazanavir, and darunavir.


InternalMed_Harrison

InternalMed_Harrison. Ritonavir was the first protease inhibitor for which clinical efficacy was demonstrated. In a study of 1090 patients with CD4+ T cell counts <100/μL who were randomized to receive either placebo or ritonavir in addition to any other licensed medications, patients receiving ritonavir had a reduction in the cumulative incidence of clinical progression or death from 34% to 17%. Mortality decreased from 10.1% to 5.8%. At full doses, ritonavir is poorly tolerated. Among the main side effects are nausea, diarrhea, abdominal pain, hyperlipidemia, and circumoral paresthesia. Ritonavir has a high affinity for several isoforms of cytochrome P450 (3A4, 2D6), and its use can result in large increases in the plasma concentrations of drugs metabolized by these pathways. Among the agents affected in this manner are most other protease inhibitors, macrolide antibiotics, R-warfarin, ondansetron, rifabutin, most calcium channel blockers, glucocorticoids, and some of the chemotherapeutic agents used to


InternalMed_Harrison

InternalMed_Harrison. manner are most other protease inhibitors, macrolide antibiotics, R-warfarin, ondansetron, rifabutin, most calcium channel blockers, glucocorticoids, and some of the chemotherapeutic agents used to treat KS and/or lymphomas. In addition, ritonavir may increase the activity of glucuronyltransferases, thus decreasing the levels of drugs metabolized by this pathway. Overall, great care must be taken when prescribing additional drugs to patients taking protease inhibitors in general and ritonavir in particular. As mentioned above, the pharmacodynamic boosting property of ritonavir, seen with doses as low as 100–200 mg once or twice a day, is often used in the setting of cART for HIV infection to derive more convenient regimens. For example, when given with low-dose ritonavir, saquinavir and indinavir can be given on twice-a-day schedules and taken with food.


InternalMed_Harrison

InternalMed_Harrison. Atazanavir is an azapeptide inhibitor of the HIV-1 protease that was licensed in 2003. An advantage of atazanavir is that total cholesterol and triglyceride levels do not increase as much with atazanavir as with other protease inhibitors. This coupled with the fact that it can be given on a once-daily schedule made atazanavir a popular component of initial treatment regimens following its licensure. Atazanavir is associated with increases in serum bilirubin, renal stones, and prolongations of the ECG PR interval. Atazanavirresistant isolates emerging in previously treatment-naïve individuals frequently harbor an I50L substitution. This mutation in some instances is associated with increased sensitivity to other protease inhibitors. Atazanavir requires an acidic gastric pH for absorption, and its use in combination with a proton pump inhibitor is contraindicated due to concerns about absorption. Atazanavir is an inhibitor of cytochrome P3A, and its use may be associated with


InternalMed_Harrison

InternalMed_Harrison. Mutations in the Reverse Transcriptase Gene Associated with Resistance to Reverse Transcriptase Inhibitors 1279 Multi-nRTI Resistance: 69 Insertion Complex (affects all nRTIs currently approved by the US FDA) Multi-nRTI Resistance: 151 Complex (affects all nRTIs currently approved by the US FDA except tenofovir) A VF FQ Multi-nRTI Resistance: Thymidine Analogue-Associated Mutations (TAMs; affect all nRTIs currently approved by the US FDA) M DK LTK L Amino acid, wild-type Amino acid position 65 100 Amino acid substitution


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 226-46 Amino acid substitutions conferring resistance to antiretroviral drugs. For each amino acid residue, the letter above the bar indicates the amino acid associated with wild-type virus and the letter(s) below indicate the substitution(s) that confer viral resistance. The number shows the position of the mutation in the protein. Mutations selected by protease inhibitors in Gag cleavage sites are not listed. HR1 indicates first heptad repeat; NAMs indicates nRTI-associated mutations; nRTI indicates nucleoside reverse transcriptase inhibitor; NNRTI indicates nonnucleoside reverse transcriptase inhibitor; PI indicates protease inhibitor. Amino acid abbreviations: A, alanine; C, cysteine; D, aspartate; E, glutamic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine. (Reprinted with permission from the


InternalMed_Harrison

InternalMed_Harrison. K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine. (Reprinted with permission from the International Antiviral Society—USA. AM Wensing, V Calvez, HR Günthard et al: 2014 Update of the Drug Resistance Mutations in HIV-1. Top Antivir Med. 2014; 22(3):642–650. Updated information [and thorough explanatory notes] is available at www.iasusa.org.)


InternalMed_Harrison

InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1280 Mutations in the Protease Gene Associated with Resistance to Protease Inhibitors Mutations in the Envelope Gene Associated with Resistance to Entry Inhibitors Maraviroc Activity limited to patients with R5 viruses


InternalMed_Harrison

InternalMed_Harrison. Mutations in the Integrase Gene Associated with Resistance to Integrase Strand Transfer Inhibitors increased levels of calcium channel blockers, macrolide antibiotics, main reasons for discontinuation were bilirubin elevations and HMG-CoA reductase inhibitors, and sildenafil. Levels of atazana-gastrointestinal side effects. vir are lower in the presence of tenofovir or efavirenz. In these Darunavir is a nonpeptidic HIV protease inhibitor initially licensed settings, levels of atazanavir should be boosted with the use of in 2006. It is indicated for coadministration with 100 mg of ritonavir low-dose ritonavir. In a head-to-head comparison, more patients and other antiretroviral agents for the treatment of HIV infecdiscontinued atazanavir than either darunavir or raltegravir. The tion. In initial studies in treatment-experienced subjects, 46% of patients achieved a reduction in HIV RNA viral loads to <50 copies/ mL. Studies in treatment-naïve patients demonstrated efficacy superior to


InternalMed_Harrison

InternalMed_Harrison. initial studies in treatment-experienced subjects, 46% of patients achieved a reduction in HIV RNA viral loads to <50 copies/ mL. Studies in treatment-naïve patients demonstrated efficacy superior to lopinavir/ritonavir-containing regimens but inferior to dolutegravir. Skin rash, which may be severe, is seen in 7% of patients and may be related to the sulfonamide moiety contained in the molecule. GI intolerance and headache are the other most frequent side effects.


InternalMed_Harrison

InternalMed_Harrison. Entry inhibitors act by interfering with the binding of HIV to its receptor or co-receptor or by interfering with the process of fusion (see above). The first drug in this class to be licensed was the fusion inhibitor enfuvirtide, or T-20, followed by the CCR5 antagonist maraviroc. A variety of additional small molecules that bind to HIV-1 co-receptors are currently in clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Enfuvirtide is a linear 36-amino-acid synthetic peptide with the N terminus acetylated and the C terminus a carboxamide. It is composed of naturally occurring L-amino acid residues and interferes with the fusion of the viral and cellular membranes by binding to the HR1 region in the gp41 subunit of the HIV-1 envelope. This binding interferes with the coil-coil interaction required to approximate the viral envelope and the host cell membrane during the process of viral fusion. Enfuvirtide was licensed in 2003 for treatment of HIV-1 infection in combination with other antiretroviral agents in treatment-experienced patients with ongoing viral replication despite antiretroviral therapy. Enfuvirtide is not active against HIV-2. Enfuvirtide-resistant isolates of HIV exhibit amino acid changes in positions 36–45 of gp41. In two independent studies, patients who had persistent viremia despite prior treatment with agents from all three available classes of drugs were randomized to receive an


InternalMed_Harrison

InternalMed_Harrison. in positions 36–45 of gp41. In two independent studies, patients who had persistent viremia despite prior treatment with agents from all three available classes of drugs were randomized to receive an individualized regimen (based on prior treatment history and resistance profile) with or without enfuvirtide. The change in plasma HIV-1 RNA from baseline was ~1 log greater (–1.53 vs –0.68) in patients randomized to receive enfuvirtide. Among the drawbacks of this agent are the requirement for twice-a-day injection, the occurrence of injection-site reactions in close to 100% of patients, and an increase in bacterial pneumonia in the enfuvirtide-treated patients compared with the control patients (4.68 vs 0.61 events per 100 patient-years) in the phase III studies.


InternalMed_Harrison

InternalMed_Harrison. Maraviroc is a CCR5 antagonist that interferes with HIV binding at the stage of co-receptor engagement. It was licensed in 2007 for treatment of HIV infection in combination with other agents in treatment-experienced patients infected with only CCR5-tropic (R5) virus resistant to multiple agents. The license was extended in 2009 to include treatment-naïve patients with R5 virus. A co-receptor tropism assay should be performed if one is considering the use of maraviroc to ensure that the potential patient is only harboring R5 viruses. In phase III trials of treatment-experienced patients randomized to receive optimal therapy plus maraviroc or placebo, 61% of patients randomized to maraviroc achieved HIV RNA levels <400 copies/mL compared with 28% of patients randomized to placebo. An allergic reaction–associated hepatotoxicity has been reported with maraviroc. Among the most common side effects of maraviroc are dizziness due to postural hypotension, cough, fever, colds, rash, muscle


InternalMed_Harrison

InternalMed_Harrison. reaction–associated hepatotoxicity has been reported with maraviroc. Among the most common side effects of maraviroc are dizziness due to postural hypotension, cough, fever, colds, rash, muscle and joint pain, and stomach pain. Maraviroc is a substrate of CYP3A and Pgp, and the recommend dose varies depending on concomitant medications. In combination with nucleoside analogues, tipranavir/ritonavir, enfuvirtide, and/or nevirapine, the dose is 300 mg twice daily. In the presence of CYP3A inhibitors, such as most protease inhibitors, the dose is 150 mg twice daily. In the presence of CYP3A inducers such as efavirenz, the dose is 600 mg twice daily.


InternalMed_Harrison

InternalMed_Harrison. Integrase inhibitors act by blocking the action of the HIV integrase enzyme and thus preventing integration of the HIV provirus into the host cell genome. They are among the most potent and safest of the antiretroviral drugs and frequently part of initial combination regimens. The three licensed integrase inhibitors are raltegravir, elvitegravir and dolutegravir.


InternalMed_Harrison

InternalMed_Harrison. Raltegravir is an inhibitor of the viral enzyme integrase and the first of this class to be approved. It acts by interfering with the binding of the preintegration complex to host DNA and as such is referred to as an integrase strand transfer inhibitor (INSTI). Raltegravir 1281 was approved in 2007 for treatment of HIV infection in combination with other agents in treatment-experienced patients, and the approval was extended in 2009 to include treatment-naïve patients. Raltegravir exhibits a wide range of activity against HIV-1 and HIV-2, including viruses with multiple resistance mutations to other classes of drugs. As with several other compounds, resistance to raltegravir comes at the expense of replicative fitness. In two phase III studies in which 436 patients with 3-class antiretroviral drug resistance were randomized to an optimized background regimen with raltegravir or placebo, 76% of patients receiving raltegravir achieved HIV RNA levels <400 copies/mL compared with 41% of


InternalMed_Harrison

InternalMed_Harrison. drug resistance were randomized to an optimized background regimen with raltegravir or placebo, 76% of patients receiving raltegravir achieved HIV RNA levels <400 copies/mL compared with 41% of patients randomized to the placebo arm. In contrast to many other antiretroviral drugs the side-effect profile of raltegravir is minimal, with similar side-effect profiles noted for the raltegravir and placebo groups.


InternalMed_Harrison

InternalMed_Harrison. Elvitegravir is an integrase inhibitor that was approved in 2012 as part of a fixed-dose combination tablet also containing tenofovir, emtricitabine, and cobicistat (Stribild). The cobicistat acts much in the same way as low-dose ritonavir to boost the concentrations of elvitegravir by inhibiting CYP3A such that once-a-day dosing of Stribild is sufficient. Elvitegravir demonstrates cross-resistance with raltegravir. In two randomized, controlled trials, elvitegravir was found to be noninferior to efavirenz in one study and noninferior to atazanavir/ritonavir in the other. The most common side effects experienced with elvitegravir are diarrhea, nausea, upper respiratory infection, and headache. The cobicistat component of the fixed-dose tablet inhibits tubular secretion of creatinine, resulting in increases in serum creatinine, and is not recommended for patients with estimated creatinine clearances <70 mL/min.


InternalMed_Harrison

InternalMed_Harrison. Dolutegravir was approved in 2013 for use as part of a combination regimen in either treatment-naïve or -experienced patients. It comes as a 50-mg tablet and is given once daily in treatment-naïve patients and twice daily in treatment-experienced patients. Isolates of HIV that have developed resistance to raltegravir or elvitegravir may still be sensitive to dolutegravir. Its main side effects are insomnia and headache. In two randomized, controlled trials it has been shown to be superior to either efavirenz (n = 833) or darunavir/ ritonavir (n = 484) in combination with nucleos(t)ide analogues due to lower rates of discontinuation. In a third trial of 822 patients it was shown to be noninferior to raltegravir.


InternalMed_Harrison

InternalMed_Harrison. The principles of therapy for HIV infection have been articulated by a panel sponsored by the U.S. Department of Health and Human Services as a working group of the NIH Office of AIDS Research Advisory Council. These principles are summarized in Table 226-23. As noted in these guidelines, cART of HIV infection does not lead to eradication or cure of HIV. The single possible exception to this is an individual with HIV infection who received an allogeneic stem cell transplant for treatment of acute myelogenous leukemia. His conditioning regimen included cytotoxic chemotherapy, total-body irradiation, and antithymocyte immunoglobulin. The donor cells were homozygous for the CCR5Δ32 mutation (see above) and thus resistant to HIV infection. Despite cART being stopped the day of the transplant, the patient has exhibited no signs of active HIV infection for more than 8 years.


InternalMed_Harrison

InternalMed_Harrison. Treatment decisions must take into account the fact that one is dealing with a chronic infection that requires daily therapy. While early therapy is generally the rule in infectious diseases, immediate treatment of every HIV-infected individual upon diagnosis may not be prudent, and therapeutic decisions must take into account the balance between risks and benefits. Patients initiating antiretroviral therapy must be willing to commit to life-long treatment and understand the importance of adherence to their prescribed regimen. The importance of adherence is illustrated by the observation that treatment interruption is associated with rapid increases in HIV RNA levels, rapid declines in CD4+ T cell counts, and an increased risk of clinical progression. While it seems reasonable to assume that the complications associated with cART could be minimized by Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1.


InternalMed_Harrison

InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1. Ongoing HIV replication leads to immune system damage, progression to AIDS, and systemic immune activation. 2. Plasma HIV RNA levels indicate the magnitude of HIV replication and the rate of CD4+ T cell destruction. CD4+ T cell counts indicate the current level of competence of the immune system. 3. Maximal suppression of viral replication is a goal of therapy; the greater the suppression the less likely the appearance of drug-resistant quasispecies. 4. The most effective therapeutic strategies involve the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents that the patient has already received. 5. The antiretroviral drugs used in combination regimens should be used according to optimum schedules and dosages. 6.


InternalMed_Harrison

InternalMed_Harrison. 5. The antiretroviral drugs used in combination regimens should be used according to optimum schedules and dosages. 6. The number of available drugs is limited. Any decisions on antiretroviral therapy have a long-term impact on future options for the patient. 7. Women should receive optimal antiretroviral therapy regardless of pregnancy status. 8. The same principles apply to children and adults. The treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations. 9. Compliance is an important part of ensuring maximal effect from a given regimen. The simpler the regimen, the easier it is for the patient to be compliant. Source: Modified from Principles of Therapy of HIV Infection, USPHS, and the Henry J. Kaiser Family Foundation.


InternalMed_Harrison

InternalMed_Harrison. Source: Modified from Principles of Therapy of HIV Infection, USPHS, and the Henry J. Kaiser Family Foundation. intermittent treatment regimens designed to minimize exposure to the drugs in question, all efforts to do so have paradoxically been associated with an increase in serious adverse events in the patients randomized to intermittent therapy, suggesting that some “nonAIDS-associated” serious adverse events such as heart attack and stroke may be linked to HIV replication. Thus, unless contraindicated for reasons of toxicity, patients started on cART should remain on cART.


InternalMed_Harrison

InternalMed_Harrison. At present, the U.S. Department of Health and Human Services Guidelines panel recommends that everyone with HIV infection be treated with cART. The evidence for this is strongest for patients with CD4+ T cell counts <350/μL. Clinical trials are underway to more carefully determine the benefit of initiating therapy in patients with CD4+ T cell counts ≥350/μL. In addition, one may wish to administer a 6-week course of therapy to uninfected individuals immediately following a high-risk exposure to HIV. The combination of tenofovir and emtricitabine is also indicated for pre-exposure prophylaxis in individuals at high risk of HIV infection. For patients diagnosed with an opportunistic infection and HIV infection at the same time, one may consider a 2to 4-week delay in the initiation of antiretroviral therapy during which time treatment is focused on the opportunistic infection. This delay may decrease the severity of any subsequent immune reconstitution inflammatory syndrome by lowering


InternalMed_Harrison

InternalMed_Harrison. therapy during which time treatment is focused on the opportunistic infection. This delay may decrease the severity of any subsequent immune reconstitution inflammatory syndrome by lowering the antigenic burden of the opportunistic infection. For patients with advanced HIV infection (CD4+ <50 cells/μL), however, cART should be initiated as soon as possible.


InternalMed_Harrison

InternalMed_Harrison. Once the decision has been made to initiate therapy, the health care provider must decide which drugs to use as the first regimen. The decision regarding choice of drugs not only will affect the immediate response to therapy but also will have implications regarding options for future therapeutic regimens. The initial regimen is usually the most effective insofar as the virus has yet to develop significant resistance. HIV is capable of rapidly developing resistance to any single agent, and therapy must be given as a multidrug combination. Given that patients can be infected with viruses that harbor drug resistance mutations, it is recommended that a viral genotype be done prior to the initiation of therapy to optimize the selection of antiretroviral agents. The combination regimens currently recommended for initial therapy in any treatment-naïve patient are listed in Table 226-24. Other regimens containing abacavir and rilpivirine may be appropriate for patients with HIV RNA levels


InternalMed_Harrison

InternalMed_Harrison. recommended for initial therapy in any treatment-naïve patient are listed in Table 226-24. Other regimens containing abacavir and rilpivirine may be appropriate for patients with HIV RNA levels <100,000 copies/ mL. It is currently unclear whether treatment-naïve individuals with


InternalMed_Harrison

InternalMed_Harrison. I. Non-Nucleoside Reverse Transcriptase Inhibitor Based: II. Protease Inhibitor Based: III. Integrase Inhibitor Based: Source: Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, USPHS.


InternalMed_Harrison

InternalMed_Harrison. <50 copies/mL of HIV RNA benefit from cART. Following the initiation of therapy one should expect a rapid, at least 1-log (tenfold) reduction in plasma HIV RNA levels within 1–2 months and then a slower decline in plasma HIV RNA levels to <50 copies/mL within 6 months. During this same time there should be a rise in the CD4+ T cell count of 100–150/μL that is also particularly brisk during the first month of therapy. Subsequently, one should anticipate a CD4+ T cell count increase of 50–100 cells/year until numbers approach normal. Many clinicians feel that failure to achieve these endpoints is an indication for a change in therapy. Other reasons for a change in therapy include a persistently declining CD4+ T cell count, a consistent increase in HIV RNA levels to >200 copies/mL, clinical deterioration, or drug toxicity (Table 226-25). As in the case of initiating therapy, changing therapy may have a lasting impact on future therapeutic options. When changing therapy because of


InternalMed_Harrison

InternalMed_Harrison. deterioration, or drug toxicity (Table 226-25). As in the case of initiating therapy, changing therapy may have a lasting impact on future therapeutic options. When changing therapy because of treatment failure (clinical progression or worsening laboratory parameters), it is important to attempt to provide a regimen with at least two new active drugs. This decision can be guided by resistance testing (see below). In the patient in whom a change is made for reasons of drug toxicity, a simple replacement of one drug is reasonable. It should be stressed that in attempting to sort out a drug toxicity it may be advisable to hold all therapy for a period of time to distinguish between drug toxicity and disease progression. Drug toxicity will usually begin to show signs of reversal within 1–2 weeks. Prior to changing a treatment regimen because of drug failure, it is important to ensure that the patient has been adherent to the prescribed regimen. As in the case of initial therapy, the


InternalMed_Harrison

InternalMed_Harrison. weeks. Prior to changing a treatment regimen because of drug failure, it is important to ensure that the patient has been adherent to the prescribed regimen. As in the case of initial therapy, the simpler the new therapeutic regimen, the easier it is for the patient to be compliant. Plasma HIV RNA levels should be monitored every 3–6 months during therapy and more frequently if one is contemplating a change in regimen due to an increase in viral load or immediately following a change in regimen.


InternalMed_Harrison

InternalMed_Harrison. In order to determine an optimal therapeutic regimen for initial therapy or for a patient on a failing regimen, one may attempt to measure antiretroviral drug susceptibility through genotyping or phenotyping of HIV quasispecies and to determine adequacy of dosing through measurement of drug levels. Genotyping may be done through cDNA sequencing. Phenotypic assays typically measure the Less than a 1-log drop in plasma HIV RNA by 4 weeks following the initiation of therapy A reproducible significant increase (defined as threefold or greater) from the nadir of plasma HIV RNA level not attributable to intercurrent infection, vaccination, or test methodology aGenerally speaking, a change should involve the initiation of at least two drugs felt to be effective in the given patient. The exception to this is when change is being made to manage toxicity, in which case a single substitution is reasonable.


InternalMed_Harrison

InternalMed_Harrison. Source: Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, USPHS.


InternalMed_Harrison

InternalMed_Harrison. enzymatic activity of viral enzymes in the presence or absence of different concentrations of different drugs and have also been used to determine co-receptor tropism. These assays will generally detect quasispecies present at a frequency of ≥10%. NextGen sequencing may allow detection of quasispecies at frequencies down to 1%. It is generally recommended that resistance testing be used in selecting initial therapy in settings where the risk of transmission of resistant virus is high (such as the United States and Europe) and in determining new regimens for patients experiencing virologic failure while on therapy. Resistance testing may be of particular value in distinguishing drug-resistant virus from poor patient compliance. Due to the rapid rate at which drug-resistant viruses revert to wild-type, it is recommended that resistance testing performed in the setting of drug failure be carried out while the patient is still on the failing regimen. Measurement of plasma drug levels can


InternalMed_Harrison

InternalMed_Harrison. wild-type, it is recommended that resistance testing performed in the setting of drug failure be carried out while the patient is still on the failing regimen. Measurement of plasma drug levels can also be used to tailor an individual treatment. The inhibitory quotient, defined as the trough blood level/IC50 of the patient’s virus, is used by some to determine the adequacy of dosing of a given treatment regimen. Despite the best of efforts there will still be patients with ongoing high levels of HIV replication while receiving the best available therapy. These patients will receive benefit from remaining on antiretroviral therapy even though it is not fully suppressive.


InternalMed_Harrison

InternalMed_Harrison. In addition to the licensed medications discussed above, a large number of experimental agents are being evaluated as possible therapies for HIV infection. Therapeutic strategies are being developed to interfere with virtually every step of the replication cycle of the virus (Fig. 226-3). In addition, as more is discovered about the role of the immune system in controlling viral replication, additional strategies, generically referred to as “immune-based therapies,” are being developed as a complement to antiviral therapy. Among the antiviral agents in early clinical trials are additional nucleoside and nucleotide analogues, protease inhibitors, fusion inhibitors, receptor and co-receptor antagonists, and integrase inhibitors as well as new antiviral strategies including antisense nucleic acids and maturation inhibitors. Among the immune-based therapies being evaluated are IFN-α, bone marrow transplantation, adoptive transfer of lymphocytes genetically modified to resist infection or


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InternalMed_Harrison. acids and maturation inhibitors. Among the immune-based therapies being evaluated are IFN-α, bone marrow transplantation, adoptive transfer of lymphocytes genetically modified to resist infection or enhance HIV-specific immunity, active immunotherapy with inactivated HIV or its components, IL-7, and IL-15.


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InternalMed_Harrison. Health care workers, especially those who deal with large numbers of HIV-infected patients, have a small but definite risk of becoming infected with HIV as a result of professional activities (see “Occupational Transmission of HIV: Health Care Workers, Laboratory Workers, and the Health Care Setting,” above). The first case of HIV transmission from a patient to health care worker was reported in 1984. Occupational transmission of HIV has been reported in most countries; as noted above, the global number of HIV infections among health care workers attributable to punctures/cuts has been estimated to be 1000 cases (range, 200–5000) per year.


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InternalMed_Harrison. In the United States 57 health care workers for whom case investigations were completed as of 2010 had documented seroconversions to HIV following occupational exposures. The routes of exposure resulting in infection were as follows: 48 percutaneous (puncture/cut injury); 5 mucocutaneous (mucous membrane and/or skin); 2 both percutaneous and mucocutaneous; and 2 of unknown route. Of the 57 health care personnel, 49 were exposed to HIV-infected blood; 3 to concentrated virus in a laboratory; 1 to visibly bloody fluid; and 4 to an unspecified fluid. The individuals with documented seroconversions included 19 laboratory workers (16 of whom were clinical laboratory workers), 24 nurses, 6 physicians, 2 surgical technicians, 1 dialysis technician, 1 respiratory therapist, 1 health aide, 1 embalmer/ morgue technician, and 2 housekeeper/maintenance workers. In addition, more than 140 possible cases of occupationally acquired HIV infection have been reported among health care personnel in the


InternalMed_Harrison

InternalMed_Harrison. morgue technician, and 2 housekeeper/maintenance workers. In addition, more than 140 possible cases of occupationally acquired HIV infection have been reported among health care personnel in the United States. The number of these workers who actually acquired their infection through occupational exposures is not known. Taken together, data from several large studies suggest that the risk of HIV 1283 infection following a percutaneous exposure to HIV-contaminated blood is ~0.3%, and after a mucous membrane exposure, ~0.09%. Although episodes of HIV transmission after nonintact skin exposure have been documented, the average risk for transmission by this route has not been precisely quantified but is estimated to be less than the risk for mucous membrane exposures. The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures. A seroprevalence survey of 3420 orthopedic


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InternalMed_Harrison. after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures. A seroprevalence survey of 3420 orthopedic surgeons, 75% of whom practiced in an area with a relatively high prevalence of HIV infection and 39% of whom reported percutaneous exposure to patient blood, usually through an accident involving a suture needle, failed to reveal any cases of possible occupational infection, suggesting that the risk of infection with a suture needle may be considerably less than that with a blood-drawing (hollow-bore) needle.


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InternalMed_Harrison. Most cases of health care worker seroconversion occur as a result of needle-stick injuries. When one considers the circumstances that result in needle-stick injuries, it is immediately obvious that adhering to the standard guidelines for dealing with sharp objects would result in a significant decrease in this type of accident. In one study, 27% of needle-stick injuries resulted from improper disposal of the needle (over half of these were due to recapping the needle), 23% occurred during attempts to start an IV line, 22% occurred during blood drawing, 16% were associated with an IM or SC injection, and 12% were associated with giving an IV infusion. Clinicians should consider potential occupational exposures to


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InternalMed_Harrison. HIV as urgent medical concerns to ensure timely postexposure management and possible administration of postexposure antiretroviral prophylaxis (PEP). Recommendations regarding PEP must take into account that a variety of circumstances determine the risk of transmission of HIV following occupational exposure. In this regard, several factors have been associated with an increased risk for occupational transmission of HIV infection, including deep injury, the presence of visible blood on the instrument causing the exposure, injury with a device that had been placed in the vein or artery of the source patient, terminal illness in the source patient, and lack of postexposure cART in the exposed health care worker. Other important considerations when considering PEP in the health care worker include known or suspected pregnancy or breast-feeding, the possibility of exposure to drug-resistant virus, and toxicities of PEP regimens. Regardless of the decision to use PEP, the wound should be


InternalMed_Harrison

InternalMed_Harrison. include known or suspected pregnancy or breast-feeding, the possibility of exposure to drug-resistant virus, and toxicities of PEP regimens. Regardless of the decision to use PEP, the wound should be cleansed immediately and antiseptic applied. If a decision is made to offer PEP, U.S. Public Health Service guidelines recommend (1) a combination of two nucleoside analogue reverse transcriptase inhibitors given for 4 weeks for less severe exposures, or (2) a combination of two nucleoside analogue reverse transcriptase inhibitors plus a third drug given for 4 weeks for more severe exposures. Most clinicians administer the latter regimen in all cases in which a decision is made to treat. Detailed guidelines are available from the Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis (CDC, 2005). The report emphasizes the importance of adherence to PEP when it is indicated, follow-up of exposed


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InternalMed_Harrison. of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis (CDC, 2005). The report emphasizes the importance of adherence to PEP when it is indicated, follow-up of exposed workers to improve PEP adherences, monitoring for adverse events (including seroconversion), and expert consultation in the management of exposures.


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InternalMed_Harrison. For consultation on the treatment of occupational exposures to HIV and other bloodborne pathogens, the clinician managing the exposed patient can call the National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) at 888-448-4911. This service is available 24 hours a day at no charge. (Additional information on the Internet is available at www.nccc.ucsf.edu.) PEPline support may be especially useful in challenging situations, such as when drug-resistant HIV strains are suspected or the health care worker is pregnant. Health care workers can minimize their risk of occupational HIV infection by following the CDC guidelines of July 1991, which include adherence to universal precautions, refraining from direct patient care if one has exudative lesions or weeping dermatitis, and disinfecting and sterilizing reusable devices employed in invasive procedures.


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1284 The premise of universal precautions is that every specimen should be handled as if it came from someone infected with a bloodborne pathogen. All samples should be double-bagged, gloves should be worn when drawing blood, and spills should be immediately disinfected with bleach. In attempting to put this small but definite risk to the health care worker in perspective, it is important to point out that ~200 health care workers die each year as a result of occupationally acquired hepatitis B infection. The tragedy in this instance is that these infections and deaths due to HBV could be greatly decreased by more extended use of the HBV vaccine. The risk of HBV infection following a needle-stick injury from a hepatitis antigen–positive patient is much higher than the risk of HIV infection (see “Transmission,” above). There are multiple examples of needle-stick injuries where the patient was positive for both HBV and HIV


InternalMed_Harrison

InternalMed_Harrison. patient is much higher than the risk of HIV infection (see “Transmission,” above). There are multiple examples of needle-stick injuries where the patient was positive for both HBV and HIV and the health care worker became infected only with HBV. For these reasons, it is advisable, given the high prevalence of HBV infection in HIV-infected individuals, that all health care workers dealing with HIV-infected patients be immunized with the HBV vaccine. TB is another infection common to HIV-infected patients that can be transmitted to the health care worker. For this reason, all health care workers should know their PPD status, have it checked yearly, and receive 6 months of isoniazid treatment if their skin test converts to positive. In addition, all patients in whom a diagnosis of TB is being entertained should be placed immediately in respiratory isolation, pending results of the diagnostic evaluation. The emergence of drug-resistant organisms, including the extensively drug-resistant


InternalMed_Harrison

InternalMed_Harrison. entertained should be placed immediately in respiratory isolation, pending results of the diagnostic evaluation. The emergence of drug-resistant organisms, including the extensively drug-resistant TB strains that have been identified in Africa, has made TB an increasing problem for health care workers. This is particularly true for the health care worker with preexisting HIV infection. One of the most charged issues ever to come between health care workers and patients is that of transmission of infection from HIV-infected health care workers to their patients. This is discussed in “Occupational Transmission of HIV: Health Care Workers, Laboratory Workers, and the Health Care Setting,” above. Theoretically, the same universal precautions that are used to protect the health care worker from the HIV-infected patient will also protect the patient from the HIV-infected health care worker.


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InternalMed_Harrison. Given that human behavior, especially human sexual behavior, is extremely difficult to change, a critical modality for preventing the spread of HIV infection is the development of a safe and effective vaccine. Historically, vaccines have provided a safe, cost-effective, and efficient means of preventing illness, disability, and death from infectious diseases. Successful vaccines for the most part are predicated on the assumptions that the body can mount an adequate immune response to the microbe or virus in question during natural infection and that the vaccine will mimic the natural response to infection. Even with serious diseases, such as smallpox, poliomyelitis, measles, and influenza among others, the body in the vast majority of cases clears the infectious agent and provides protection, which is usually life-long against future exposure. Unfortunately, this is not the case with HIV infection since the natural immune response to HIV infection is unable to clear the virus from the


InternalMed_Harrison

InternalMed_Harrison. which is usually life-long against future exposure. Unfortunately, this is not the case with HIV infection since the natural immune response to HIV infection is unable to clear the virus from the body and cases of superinfection are not uncommon. Some of the factors that contribute to the problematic nature of development of a preventive HIV vaccine are the high mutability of the virus, the fact that the infection can be transmitted by cell-free or cell-associated virus, the fact that the HIV provirus integrates itself into the genome of the target cell and may remain in a latent form unexposed to the immune system, the likely need for the development of effective mucosal immunity, and the fact that it has been difficult to establish the precise correlates of protective immunity to HIV infection. A fraction of a percent of HIV-infected individuals are “elite controllers” in that they maintain extremely low and even undetectable levels of viremia in the absence of cART, and a number of


InternalMed_Harrison

InternalMed_Harrison. A fraction of a percent of HIV-infected individuals are “elite controllers” in that they maintain extremely low and even undetectable levels of viremia in the absence of cART, and a number of individuals have been exposed to HIV multiple times but remain uninfected; these facts suggest that there are elements of host defense or an HIV-specific immune response that have the potential to be protective. Early attempts to develop a vaccine with the envelope protein gp120 aimed at inducing neutralizing antibodies in humans were unsuccessful in that the elicited antisera failed to neutralize primary isolates of HIV cultured and tested in fresh peripheral blood mononuclear cells. In this regard, two phase 3 trials were undertaken in the United States and Thailand using soluble gp120, and the vaccines failed to protect human volunteers from HIV infection. In addition, two separate vaccine trials aimed at eliciting CD8+ T cell responses to prevent infection and, if unsuccessful in preventing


InternalMed_Harrison

InternalMed_Harrison. failed to protect human volunteers from HIV infection. In addition, two separate vaccine trials aimed at eliciting CD8+ T cell responses to prevent infection and, if unsuccessful in preventing infection to control postinfection viremia, also failed at both goals. Recently, a vaccine using a poxvirus vector prime expressing various viral proteins followed by an envelope protein boost was tested in a 16,000-person clinical trial (RV144) conducted in Thailand among predominantly low-prevalence heterosexuals. The vaccine provided the first positive, albeit very modest, signal ever reported in an HIV vaccine trial, showing 31% protection against acquisition of infection. Such a result is certainly not sufficient justification for clinical use of the vaccine, but it served as an important first step in the direction of the development of a safe and effective vaccine against HIV infection. Follow-up studies of RV144 indicate that nonneutralizing or weakly neutralizing antibody responses


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InternalMed_Harrison. step in the direction of the development of a safe and effective vaccine against HIV infection. Follow-up studies of RV144 indicate that nonneutralizing or weakly neutralizing antibody responses against certain constant epitopes in the otherwise highly variable V1-V2 region of the HIV envelope may be associated with the modest degree of protection observed in that clinical trial. Additional studies are planned in attempts to improve on the results of RV144 by a variety of approaches, including increasing the number of vaccine boosts with envelope protein.


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InternalMed_Harrison. An area of HIV vaccine research that is currently being actively pursued is the attempt to induce broadly neutralizing antibodies by developing as immunogens for vaccination certain epitopes on the HIV envelope that are the targets of naturally occurring broadly neutralizing antibodies during HIV infection. It is curious that only about 20% of HIV-infected individuals develop broadly neutralizing antibodies in response to natural infection and they do so only after 2 to 3 years of ongoing infection. By the time these antibodies appear, they can neutralize a broad range of primary HIV isolates, but they appear to be ineffective against the autologous virus in the infected subject. Upon close examination, these broadly neutralizing antibodies manifest a high degree of somatic mutations that were accumulated over time and are responsible for their affinity maturation and broadly neutralizing capacity. The goal of current efforts is to develop the conformationally correct HIV envelope


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InternalMed_Harrison. were accumulated over time and are responsible for their affinity maturation and broadly neutralizing capacity. The goal of current efforts is to develop the conformationally correct HIV envelope epitopes that, when used as immunogens, would direct the immune response of an uninfected individual to the production of broadly neutralizing antibodies over a reasonable time frame by sequential immunizations. It remains to be seen whether this approach will be feasible.


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InternalMed_Harrison. Education, counseling, and behavior modification are the cornerstones of any HIV prevention strategy. A major problem in the United States and elsewhere is that many infections are passed on by those who do not know that they are infected. Of the ~1.1 million persons in the United States who are HIV-infected, it is estimated that ~16–18% do not know their HIV status and approximately 49% of all new infections are transmitted by those people who are not aware that they are infected. In this regard, the CDC has recommended that HIV testing become part of routine medical care and that all individuals between the ages of 13 and 64 years be tested at least one time. These individuals should be informed of the testing and be tested without the need for written informed consent. Each individual could “opt out” of testing, but testing would otherwise be routinely administered. Individuals who are practicing high-risk behavior should be tested more often. In addition to identifying individuals


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InternalMed_Harrison. “opt out” of testing, but testing would otherwise be routinely administered. Individuals who are practicing high-risk behavior should be tested more often. In addition to identifying individuals who might benefit from cART, information gathered from such an approach should serve as the basis for behavior-modification programs, both for infected individuals who may be unaware of their HIV status and who could infect others and for uninfected individuals practicing high-risk behavior. The practice of “safer sex” is the most effective way for sexually active uninfected individuals to avoid contracting HIV infection and for infected individuals to avoid spreading infection. Abstinence from sexual relations is the only absolute way to prevent sexual transmission of HIV infection. However, for many individuals this may not be feasible, and there are a number of relatively safe practices that can markedly decrease the chances of transmission of HIV infection. Partners engaged in monogamous


InternalMed_Harrison

InternalMed_Harrison. many individuals this may not be feasible, and there are a number of relatively safe practices that can markedly decrease the chances of transmission of HIV infection. Partners engaged in monogamous sexual relationships who wish to be assured of safety should both be tested for HIV antibody. If both are negative, it must be understood that any divergence from monogamy puts both partners at risk; open discussion of the importance of honesty in such relationships should be encouraged. When the HIV status of either partner is not known, or when one partner is positive, there are a number of options. Use of condoms can markedly decrease the chance of HIV transmission. It should be remembered that condoms are not 100% effective in preventing transmission of HIV infection, and there is a ~10% failure rate of condoms used for contraceptive purposes. Most condom failures result from breakage or improper usage, such as not wearing the condom for the entire period of intercourse. Latex condoms


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InternalMed_Harrison. rate of condoms used for contraceptive purposes. Most condom failures result from breakage or improper usage, such as not wearing the condom for the entire period of intercourse. Latex condoms are preferable, since virus has been shown to leak through natural skin condoms. Petroleum-based gels should never be used for lubrication of the condom, since they increase the likelihood of condom rupture. Some men who have sex with men practice fellatio as a “minimal risk” activity compared with anal intercourse. It should be emphasized that receptive fellatio is definitely not safe sex, and although the incidence of transmission via fellatio is considerably less than that of rectal or vaginal intercourse, there has been documentation of transmission of HIV where receptive fellatio was the only sexual act performed (see “Transmission,” above). Topical microbicides composed of gels containing antiretroviral drugs have been shown to be efficacious in preventing acquisition of HIV infection in


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InternalMed_Harrison. sexual act performed (see “Transmission,” above). Topical microbicides composed of gels containing antiretroviral drugs have been shown to be efficacious in preventing acquisition of HIV infection in women engaging in vaginal intercourse. However, there has been a considerable degree of variability in efficacy related to the variable adherence of participants to the use of the intervention. In general, it is felt that microbicides can be quite efficacious; however, adherence is a major stumbling block to 1285 their broad effectiveness. Pre-exposure prophylaxis (PreP) using oral antiretroviral drugs on a daily basis in uninfected men who have sex with men and transgender women has been shown to be efficacious in preventing acquisition of HIV infection. The degree of efficacy can be very high (>90%) if subjects adhere strictly to the regimen. However, adherence has proven to be a problem in maximizing the overall effectiveness of this approach.


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InternalMed_Harrison. Adult male circumcision has been shown to result in a 50% to 65% reduction in HIV acquisition in the circumcised subject. Clearly, this approach has considerable potential as a preventive strategy for HIV infection and is currently being pursued, particularly in developing nations, as a component of HIV prevention. The most effective way to prevent transmission of HIV infection among IDUs is to stop the use of injectable drugs. Unfortunately, that is extremely difficult to accomplish unless the individual enters a treatment program. For those who will not or cannot participate in a drug treatment program and who will continue to inject drugs, the avoidance of sharing of needles and other paraphernalia (“works”) is the next best way to avoid transmission of infection. However, the cultural and social factors that contribute to the sharing of paraphernalia are complex and difficult to overcome. In addition, needles and syringes may be in short supply. Under these circumstances,


InternalMed_Harrison

InternalMed_Harrison. cultural and social factors that contribute to the sharing of paraphernalia are complex and difficult to overcome. In addition, needles and syringes may be in short supply. Under these circumstances, paraphernalia should be cleaned after each usage with a virucidal solution, such as undiluted sodium hypochlorite (household bleach). Programs that provide sterile needles to addicts in exchange for used needles have resulted in a marked decrease in HIV transmission without increasing the use of injection drugs. It is important for IDUs to be tested for HIV infection and counseled to avoid transmission to their sexual partners. Oral PreP also is effective in preventing acquisition of HIV infections among IDUs. Prevention of transmission through blood or blood products and prevention of mother-to-child transmission are discussed in “Transmission,” above.


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InternalMed_Harrison. Umesh D. Parashar, Roger I. Glass Acute infectious gastroenteritis is a common illness that affects persons of all ages worldwide. It is a leading cause of mortality among children in developing countries, accounting for an estimated 0.7 million deaths each year, and is responsible for up to 10–12% of all hospitalizations among children in industrialized countries, including the United States. Elderly persons, especially those with debilitating health conditions, also are at risk of severe complications and death from acute gastroenteritis. Among healthy young adults, acute gastroenteritis is rarely fatal but incurs substantial medical and social costs, including those of time lost from work.