1583CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

the response rate for patients with counts <150/μL is <10%. In contrast

to the other systemic therapies, IFN-α provides an added advantage of

having antiretroviral activity; thus, it may be the appropriate first choice

for single-agent systemic therapy for early patients with disseminated

disease. A variety of chemotherapeutic agents also have been shown

to have activity against KS. Five of them—liposomal daunorubicin,

liposomal doxorubicin, vinblastine, paclitaxel, and the thalidomide

analogue pomalidomide—have been approved by the FDA for this

indication. Liposomal daunorubicin and pomalidomide are approved

as first-line therapy for patients with advanced KS despite ART. They

have fewer side effects than conventional chemotherapy. In contrast,

liposomal doxorubicin and paclitaxel are approved only for KS patients

who have failed standard chemotherapy. Response rates vary from 23

to 88%, appear to be comparable to what had been achieved earlier

with combination chemotherapy regimens, and are greatly influenced

by CD4+ T-cell count. Vinblastine is most commonly used as an intralesional injection or as part of a combination regimen.

Lymphomas occur with an increased frequency in patients with

congenital or acquired T-cell immunodeficiencies (Chap. 344). AIDS

is no exception; at least 6% of all patients with AIDS develop lymphoma at some time during the course of their illness. This is a 10- to

20-fold increase in incidence compared with the general population. In

contrast to the situation with KS, primary CNS lymphoma, and most

opportunistic infections, the incidence of AIDS-associated systemic

lymphomas has not experienced a dramatic decrease as a consequence

of the widespread use of effective ART. Lymphoma occurs in all risk

groups, with the highest incidence in patients with hemophilia and

the lowest incidence in patients from the Caribbean or Africa with

heterosexually acquired infection. Lymphoma is a late manifestation of

HIV infection, generally occurring in patients with CD4+ T-cell counts

<200/μL. As HIV disease progresses, the risk of lymphoma increases.

The attack rate for lymphoma increases exponentially with increasing duration of HIV infection and decreasing level of immunologic

function. At 3 years following a diagnosis of HIV infection, the risk

of lymphoma is 0.8% per year; by 8 years after infection, it is 2.6% per

year. As individuals with HIV infection live longer as a consequence

of improved ART and better treatment and prophylaxis of opportunistic infections, it is anticipated that the incidence of lymphomas may

increase.

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.

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

KSHV 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).

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 chromosome

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.

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.

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. 202-44) 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, and/

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 3- to 5-cm lesions (Fig. 202-45). 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. Lesions of CNS lymphoma

are most commonly seen 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.

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.

FIGURE 202-44 Immunoblastic lymphoma involving the hard palate of a patient

with AIDS.

1584 PART 5 Infectious Diseases

Both conventional and unconventional approaches have been

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 ART 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 ART are mitigated with the use of ART 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 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%.

Multicentric Castleman’s disease (MCD) is a KSHV-associated lymphoproliferative disorder that is seen with an increased frequency in

patients with HIV infection. While the incidence of Kaposi’s sarcoma

has decreased, the incidence of MCD has increased in the setting

of ART. While not a true malignancy, MCD 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 predominance of interfollicular plasma cells and/or germinal centers with vascularization and

an “onion skin” (hyaline vascular) appearance. Prior to the availability

of ART, HIV-infected patients with multicentric Castleman’s disease

had a 15-fold increased risk of developing non-Hodgkin’s lymphoma

compared with HIV-infected patients in general. Treatment typically

involves chemotherapy. Rituximab may be of benefit, but it has been

associated with worsening of coexisting KS. The median survival of

patients with treated multicentric Castleman’s disease pre-ART was

initially reported as 14 months. This has increased to a 2-year survival

of more than 90% in the era of ART.

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 ART, 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 conditions when one compares

HIV-infected to noninfected men and women is on the order of 10- to

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

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 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. In the HIV-infected population other genotypes such as 58 and 53 are also prominent. This raises a concern 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.

IDIOPATHIC CD4+ T LYMPHOCYTOPENIA

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. 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. However, as a result of immune deficiency,

certain patients with ICL develop some of the opportunistic diseases

(particularly cryptococcosis, nontuberculous mycobacterial infections,

and HPV disease) seen in HIV-infected patients. Approximately 10%

of patients may exhibit an autoimmune disease. 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 initially diagnosed

patients did have risk factors probably reflects a selection bias, in that

physicians who take care of HIV-infected patients were 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 may 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

FIGURE 202-45 Central nervous system lymphoma. Postcontrast T1-weighted

MRI scan in a patient with AIDS, 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.

1585CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

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,

HIV-2, 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.

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.

TREATMENT

AIDS and Related Disorders

 GENERAL PRINCIPLES OF PATIENT MANAGEMENT

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 13% of the 1.2 million individuals in the United States who are HIV-infected are not aware of

their status. In the setting of routine testing, although it is difficult,

pretest counseling is an important part of the process. 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, utilize 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 and initiate ART. These supports should include individuals

who can spend time talking to the newly diagnosed person and

ensuring that he or she is emotionally stable and ready to begin

therapy. Most communities have HIV support centers that can be

of great help in these difficult situations.

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

ART, 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. The appropriate use of potent ART

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 with HIV infection. In contrast to the

earlier days of this epidemic, a diagnosis of HIV infection needs

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

only a reflection of the sensitivity of the assay being used to measure

the virus, rather 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 in virtually all patients who have ever been diagnosed with

HIV infection and capable of being transmitted in the absence of

effective ART. 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, listen to their concerns, and be sensitive to

their fears. 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.

Following a diagnosis of HIV infection, several examinations

and laboratory studies should be performed to help determine the

extent of disease and provide baseline standards for future reference

(Table 202-19). 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, a plasma HIV RNA level, 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 people whom

the patient knows, or suspects, may also be infected. Once these

baseline activities are performed, short- and 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

TABLE 202-19 Initial Evaluation of the Patient with HIV Infection

History and physical examination

Routine chemistry and hematology

AST, ALT, alkaline phosphatase, direct and indirect bilirubin

Lipid profile and fasting glucose

CD4+ T lymphocyte count

Plasma HIV RNA level

HIV resistance testing

HLA-B5701 screening

RPR or VDRL test

Anti-Toxoplasma antibody titer

Urinalysis

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; HPV 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.

1586 PART 5 Infectious Diseases

TABLE 202-20 HIV Disease Resources Available on the

World Wide Web

www.hivinfo.nih.gov HIVinfo 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.

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 202-20).

ANTIRETROVIRAL THERAPY

Combination antiretroviral therapy (ART), also referred to as highly

active antiretroviral therapy (HAART), is the cornerstone of management of patients with HIV infection and should be initiated as

soon as possible following a diagnosis of HIV infection. One exception to immediate initiation of ART is in the setting of cryptococcal

or TB meningitis where several weeks of specific antimicrobial therapy prior to initiation of ART may decrease the risk of severe IRIS.

Following the initiation of widespread use of ART in the United

States in 1995–1996, marked declines were noted in the incidence

of most AIDS-defining conditions (Fig. 202-34). Suppression of

HIV replication is an important component in prolonging and

improving the quality of life for the patient as well as minimizing

the risk of transmission of HIV to others. Adequate suppression of

HIV replication requires strict adherence to prescribed regimens of

antiretroviral drugs. This has been facilitated by the coformulations

of antiretrovirals and the development of once-daily and monthly

regimens. Unfortunately, many of the most important questions

related to the treatment of HIV disease currently lack definitive

answers. Among the decisions that need to be made in the context

of prescribing ART are selection of the best initial regimen, determining when a given regimen should be changed, and deciding

what regimen should be selected when a change is made. The care

provider 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 (https://clinicalinfo.hiv.gov/en/guidelines) 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 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

ART are best made in consultation with experts.

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 negative strand transfer inhibitors),

and those that interfere with viral entry (fusion inhibitors; CCR5

antagonists; CD4 antagonists) (Table 202-21; Fig. 202-46). A typical

initial regimen will include two nucleoside/nucleotide reverse transcriptase inhibitors (usually a tenofovir-based drug or abacavir +

3TC or FTC) plus a nonnucleoside reverse transcriptase inhibitor,

an integrase inhibitor, or a protease inhibitor boosted with a pharmacokinetic enhancer (ritonavir or cobicistat). More recent studies

have also supported the two-drug regimen of dolutegravir plus 3TC

for initial therapy in hepatitis B–negative patients with baseline

HIV RNA levels under 500,000 copies/mL. Numerous fixed-drug

formulations combining two or more of these antiretroviral drugs

have been licensed (Table  202-22). Prior to initiation of therapy

and at any time a change in therapy due to treatment failure is being

considered, drug resistance testing should be performed to help

guide the selection of drugs to be used in combination. A summary

of known resistance mutations for antiretroviral drugs is shown in

Fig. 202-47.

While most patients with HIV infection will be infected with

HIV-1, some patients, especially those with an epidemiologic link

to West Africa, may be infected with HIV-2. While the principles

of treatment are the same as those for persons infected with HIV-1,

it is important to note that the nonnucleoside reverse transcriptase

inhibitors enfuvirtide and fostemsavir are not active against HIV-2

and should not be used as part of ART regimens in HIV-2–infected

individuals.

The FDA-approved reverse transcriptase inhibitors include the

nucleoside analogues zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, and emtricitabine; the nucleotide analogues tenofovir disoproxil and tenofovir alafenamide; and the

nonnucleoside reverse transcriptase inhibitors nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, long-acting rilpivirine, and

doravirine (Table 202-21). 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. Similarly, when

any of these three  medications are discontinued, one needs to be

vigilant for a flare of hepatitis B in coinfected patients. 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 Disorders,” above). For these

reasons, the older drugs in this class, zidovudine, didanosine, zalcitabine, and stavudine are no longer recommend for use in the

United States due to their side effect profiles. The nucleoside and

nucleotide transcriptase inhibitors preferred for use in combination

regimens according to the DHHS Panel on the use of antiretroviral

drugs are lamivudine, emtricitabine, abacavir, tenofovir disoproxil,

and tenofovir alafenamide. Given its renal toxicity, tenofovir disoproxil should be limited to use in patients with creatinine clearance

(CrCl) >70 while tenofovir alafenamide should generally be limited

to use in patients with CrCl >30. The preferred nonnucleoside

reverse transcriptase inhibitors are efavirenz, rilpivirine, and doravirine. Of note, rilpivirine is approved for treatment only in ARTnaïve patients with HIV RNA levels <100,000 copies/mL and is

contraindicated in patients taking proton pump inhibitors.