Management of The Patient With HIV Desease

Management of the Patient with HIV
Disease
Surendra K. Sharma, MD, PhD, and
Tamilarasu Kadhiravan, MD
Introduction
AIDS was described initially in the United States in 1981 among several
case clusters of previously healthy young men who had sex with men,
presenting with unusual infections such as Pneumocystis jiroveci pneumonia (PCP), mucosal candidiasis, disseminated cytomegalovirus (CMV)
disease, and Kaposis sarcoma. The cause of AIDS remained elusive then,
leading to several speculations. A few years later, amid much controversy, the causative agent was established as HIV, which has a predilection to infect and destroy the immune effector cells, primarily the CD4
T lymphocytes. The discovery of HIV led to the development of definitive
diagnostic tests that unearthed, to everyones dismay, a widespread,
hitherto invisible, smoldering pandemic in evolution.
Epidemiology
Since the beginning of the epidemic, approximately 25 million people
have died of AIDS worldwide, making it one of the most devastating
epidemics of all times. An estimated 40 million people are living with
HIV/AIDS globally, including 17.5 million women and 2.3 million
children younger than 15 years. In 2005 alone, an estimated 5 million
people were newly infected, and approximately 3 million people died
because of AIDS. More than half of the burden of HIV/AIDS is borne by
sub-Saharan Africa, particularly the southern African nations. In countries such as Botswana, South Africa, Zimbabwe, Swaziland, and Namibia, the prevalence of HIV infection among expectant mothers is
consistently in excess of 20%.
North America accounts for approximately 1.2 million people living
with HIV/AIDS, most of them in the United States. Every year, more than
This article was published in: Rakel RE, Bope ET. Conns Current Therapy 2008. Section 2: The
Infectious Diseases. Management of the Patient with HIV Disease, p. 47-61. 2008 Elsevier Inc.
Dis Mon 2008;54:162-195
0011-5029/2008 $34.00 0
doi:10.1016/j.disamonth.2007.12.002
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DM, March 2008
35,000 new cases are reported in the United States. Blacks and Hispanics
are disproportionately represented among them, and pediatric AIDS
accounts for approximately 1% of the cases. With the widespread
implementation of preventive measures, a marginal but significant fall in
HIV infection rates was observed for the first time among non-Hispanic
blacks and injection drug users.
The Causative Agent

HIV is an enveloped single-stranded RNA virus (family, Retroviridae;
subfamily, Lentivirinae). Embedded in its envelope are glycoprotein
spikes (gp120, gp41) that are crucial for binding with the host cell surface
receptors, such as CD4, CCR5, and CXCR4, and subsequent entry into
the host cell. HIV is a retrovirus that elaborates the enzyme reverse
transcriptase. It enables transcription of genomic RNA to proviral DNA
for integration into the host cell DNA. Host cells that bear CD4 (helper
T cells, macrophages, etc.) are the main targets of HIV infection. There
are two human immunodeficiency viruses: HIV-1 and HIV-2. Compelling
genetic evidence suggests that they originated from the simian immunodeficiency viruses, of the chimpanzee (SIVcpz) and the sooty mangabey
monkeys (SIVsm), respectively, in Africa several decades back. HIV-1 is
global in distribution, whereas HIV-2 is confined mainly to western
Africa. HIV-2 infection is less effectively transmitted and results in lower
levels of viremia and slower disease progression compared with HIV-1.
Isolates of HIV-1 across the globe exhibit marked genetic heterogeneity
and are classified into three groups (M, O, and N) and several clades.
Clade C is the most common form worldwide. In North America and
Europe, clade B is the predominant subtype. Genetic recombination
among co-circulating clades often occurs, and such a recombinant
subtype AE is the most prevalent form in Southeast Asia. Clade AE
viruses are transmitted more effectively by the heterosexual route than the
clade B virus. The genetic heterogeneity of HIV has to be taken into
consideration in the development and evaluation of HIV vaccines.
Modes of Transmission
Transmission of HIV occurs through contact with the body fluids of a
HIV-infected person. The routes of transmission are sexual, both maleto-male as well as heterosexual contact; mother-to-child; transfusion of
HIV-tainted blood and blood products; injection drug use; and occupational exposure in health care and laboratory workers. No evidence
suggests that HIV is transmitted by casual contact and insect bites.
Heterosexual transmission is the most prevalent route of HIV transmisDM, March 2008
163
sion worldwide, especially in developing countries. In the United States,

male-to-male sexual contact is the most common route of transmission;
however, the proportion of cases caused by heterosexual transmission is
steadily increasing.
The average risk of HIV transmission per coital act in sero-discordant
heterosexual couples is approximately 0.1%. Several factors, such as the
presence of other sexually transmitted infections (ulcerative as well as
nonulcerative) and higher viral load, increase the risk of transmission;
condom use and male circumcision considerably reduce the risk. Femaleto-male transmission is less effective than male-to-female transmission.
Commercial sex is associated with a higher risk of transmission of
approximately 5% to 10%. Receptive anal intercourse is associated with
a higher risk of transmission as compared with vaginal intercourse. Even
though the risk of transmission by oral sex is very low, it should not be
considered completely safe.
Mother-to-child transmission of infection can occur during pregnancy,
during delivery, or by breastfeeding. More than half of the transmissions
occur intrapartum, mediated by direct contact of infant mucosa with
HIV-laden maternal blood, amniotic fluid, and cervical/vaginal secretions. Placental microtransfusion also plays a role. High maternal plasma
viremia, prolonged rupture of membranes, and chorioamnionitis increase
the risk of mother-to-child transmission, whereas cesarean delivery and
use of peripartum antiretroviral prophylaxis decrease the risk markedly.
With the implementation of mandatory testing practices, transmission
through infected blood and blood products is almost eliminated in the
developed world. However, despite using the highly sensitive nucleic
acid-based tests, given the enormous number of transfusions in clinical
practice, the risk of transfusion-transmitted HIV infection cannot be
overlooked. It is estimated that each year 16 infectious donations are
available for transfusion in the United States.
Although injection drug use is responsible for approximately 20% of
HIV transmission in the United States, it is the driving force behind the
HIV epidemic in Southeast Asian countries and China. Apart from direct
transmission through sharing of contaminated needles and other paraphernalia, injection drug use also promotes risk-taking behavior and unsafe
sexual practices. In developing countries, unsafe injections administered
at health care facilities are a potential, but underappreciated, route of HIV
transmission. Occupational transmission occurs through percutaneous
needle stick injuries and after mucous membrane or nonintact skin
exposure to infected body fluids. The risk of HIV infection following a
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TABLE 1. Acute HIV Syndrome*

Clinical Features
Differential Diagnosis
Common (50%)
Fever
Malaise
Lymphadenopathy
Pharyngitis
Rasherythematous, maculopapular; urticarial;
mucocutaneous ulcers
Myalgia and arthralgia
Frequent (10%50%)
Diarrhea
Headache
Nausea and vomiting
Hepatosplenomegaly
Oral thrush
Anorexia and weight loss
Occasional (10%)
Aseptic meningitis
Acute meningoencephalitis
Guillain-Barr syndrome
Myelopathy
Brachial neuritis
Facial palsy
Peripheral neuropathy
Opportunistic infections
Infectious mononucleosis
Acute cytomegalovirus infection
Secondary syphilis
Acute toxoplasmosis
Rickettsial infections
Rubella
Systemic lupus erythematosus
Stills disease
*Occurs approximately 3 6 wk following primary infection; symptoms last for 1 to several

weeks, followed by gradual, spontaneous resolution; in a small proportion (approximately
10%), despite resolution of initial symptoms, rapid immunologic deterioration follows.
contaminated needle stick injury is approximately 0.3% and is approximately 0.09% following mucous membrane exposure.
Pathogenesis and Natural History of HIV Infection

Following infection, HIV localizes to the lymphoid organs of the body,
where it productively infects the CD4 helper T lymphocytes in the
milieu provided by the dendritic cells and subsequently spills over into
the circulation. In the absence of an immune response, this results in
intense viremia in the early weeks following primary infection. During
this phase, extensive dissemination of the virus occurs throughout the
body. In approximately 50% to 70% of individuals, this might become
clinically manifest as a self-limited, mononucleosis-like illness known as
acute HIV syndrome (Table 1). Soon, with the elaboration of HIVspecific cell-mediated as well as humoral immune responses, viremia is
brought under control albeit incompletely. A balance thus is struck
between the opposing influences of viremia and the host immune
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165
response, establishing the viral load around a relatively low, stable level
known as the virologic setpoint. The virologic setpoint is one of the
important determinants of the pace of subsequent disease progression.
Even if the viremia gets suppressed to below-detectable limits, despite the
disease being clinically silent, active viral replication occurs throughout
the course of HIV disease.
Some aspects of viral dynamics in vivo are important from a therapeutic
point of view. An enormously large amount of virions (1010 to 1011) are
produced and cleared every day. Thus, the chances of a drug-resistant
strain emerging under the selection pressure exerted by antiretroviral
therapy are very high. Even in patients who achieve undetectable viral
loads for prolonged periods of time following treatment, ongoing active
viral replication occurs. If therapy is stopped in these patients, viral load
promptly bounces back. Further, antiretroviral therapy does not eliminate
the large reservoir of latently infected cells that are capable of giving rise
to replication-competent virus. Theoretically, it would take several
decades of uninterrupted viral suppression for this reservoir to get
depleted on its own.
During the phase of clinical latency, continuous viral replication leads
to progressive depletion of CD4 helper T cells, resulting from direct
cytopathicity as well as by diverse indirect mechanisms. When the CD4
cell count falls below 200 cells/mL, the risk of opportunistic infections
(OIs) increases greatly, culminating in AIDS. The CD4 cell count, as an
index of immunosuppression because of HIV infection, predicts strongly
the risk of OIs and thereby the risk of progression to AIDS and
subsequent death (Table 2). However, when the CD4 counts are above
350 cells/mL, their usefulness in predicting the risk of disease progression
is limited. Conversely, the plasma viral load is a more robust predictor of
the risk of AIDS, independent of the CD4 count at all levels (Table 2).
The rate of decline in CD4 count is highly variable among individuals.
Some progress very rapidly, whereas a few others maintain normal levels
of CD4 counts and immunocompetence for prolonged periods without
treatment. In Western populations, the median time to development of
AIDS is approximately 10 years, and approximately 10% of patients
remain asymptomatic beyond 20 years. The latter are known as long-term
nonprogressors.
Apart from the viral load, several host-related factors also influence the
rate of disease progression. It is well known that people who are
homozygous for the deletion mutation CCR5-32, which codes for a
nonfunctional CCR5, are highly resistant to HIV infection despite
repeated exposure. HIV-infected individuals who are heterozygous for
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DM, March 2008
TABLE 2. Predicted 6-Month Risk of AIDS in the CASCADE Project, Based on Age, Current CD4
Count, and Plasma Viral Load
Predicted Risk at Current CD4 Cell Count (cells/L)
Viral Load
(copies/mL)
50
100
150
3,000
10,000
30,000
100,000
300,000
6.8
9.6
13.3
18.6
25.1
3.7
5.3
7.4
10.6
14.5
2.3
3.4
4.7
6.7
9.3
3,000
10,000
30,000
100,000
300,000
8.5
12.1
16.6
23.1
30.8
4.7
6.7
9.3
13.2
18.0
3.0
4.3
5.9
8.5
11.7
3,000
10,000
30,000
100,000
300,000
10.7
15.1
20.6
28.4
37.4
5.9
8.5
11.7
16.5
22.4
3.7
5.4
7.5
10.6
14.6
3,000
10,000
30,000
100,000
300,000
13.4
18.8
25.4
34.6
44.8
7.5
10.7
14.6
20.5
27.5
4.7
6.8
9.4
13.3
18.2
200
250
Age 25
1.6
2.3
3.2
4.6
6.3
Age 35
2.0
2.9
4.0
5.8
8.0
Age 45
2.5
3.6
5.1
7.3
10.1
Age 55
3.2
4.6
6.4
9.2
12.6
y
1.1
1.6
2.2
3.2
4.5
y
1.4
2.0
2.8
4.1
5.7
y
1.8
2.6
3.6
5.2
7.2
y
2.3
3.3
4.6
6.5
9.1
300
350
400
450
500
0.8
1.2
1.6
2.4
3.3
0.6
0.9
1.2
1.8
2.5
0.5
0.7
0.9
1.4
1.9
0.4
0.5
0.7
1.1
1.5
0.3
0.4
0.6
0.8
1.2
1.0
1.5
2.1
3.0
4.2
0.8
1.1
1.6
2.3
3.1
0.6
0.9
1.2
1.7
2.4
0.5
0.7
0.9
1.3
1.9
0.4
0.5
0.7
1.1
1.5
1.3
1.9
2.6
3.8
5.3
1.0
1.4
2.0
2.9
4.0
0.7
1.1
1.5
2.2
3.1
0.6
0.8
1.2
1.7
2.4
0.5
0.7
0.9
1.3
1.9
1.7
2.4
3.3
4.8
6.7
1.2
1.8
2.5
3.6
5.0
0.9
1.4
1.9
2.8
3.9
0.7
1.1
1.5
2.2
3.0
0.6
0.8
1.2
1.7
2.4
Note: Shading distinguishes risk: 2% no shading; 2%9.9% light gray; 10%19.9%

midgray; 20% dark gray.
Abbreviation: CASCADE Concerted Action on Seroconversion to AIDS and Death in Europe.
Reproduced with permission from Phillips A; CASCADE collaboration: Short-term risk of AIDS
according to current CD4 cell count and viral load in antiretroviral drug-nave individuals and
those treated in the monotherapy era. AIDS 2004;18(1):5158.
this allele have comparatively lower plasma viral loads and slower rate of
progression to AIDS. Likewise, homo/heterozygosity for the mutant
allele CCR2 64I, the product of which dimerizes with and decreases the
expression of CXCR4 on the cell surface, results in slower disease
progression. HLA alleles B*5701 and B*2705 also are strongly associated with long-term nonprogressor status. Conversely, individuals having
the single nucleotide polymorphism at the promoter site of the inhibitory
cytokine IL-10 (IL-10-5=-592A) are at a higher risk for HIV infection
upon exposure, and they progress to AIDS more rapidly once infected.
Certain exogenous factors might also influence the course of HIV
infection. The orphan virus GB virus C slows down disease progression
and is associated with better survival in patients dually infected with HIV
DM, March 2008
167
and GB virus C. CMV co-infection possibly augments the rate of HIV

disease progression. Incident OIs, especially tuberculosis and deficiency
of micronutrients, also accelerate disease progression.
Changing Face of HIV/AIDS

Highly active antiretroviral therapy (HAART) has dramatically changed
the long-term outcome of patients with HIV/AIDS, which once was a
rapidly fatal illness. HAART not only improves the CD4 counts but
also decreases the risk of OIs and reduces the mortality substantially. The
benefit of HAART is evident even in those patients with advanced
immunosuppression. From a public health perspective, HAART is a
cost-effective intervention, in the developed world and the developing
nations alike. In fact, HAART is comparatively more cost-effective than
some of the widely accepted therapies for certain non-HIV diseases.
Since the introduction of HAART in 1995, AIDS-related mortality has
declined considerably in the United States. With improved survival of
patients with AIDS, noninfectious complications of AIDS such as
AIDS-related malignancies and chronic renal failure are increasingly
seen. Similarly, some novel problems of long-term antiretroviral therapy,
such as lipodystrophy, insulin-resistance syndrome, increased risk of
cardiovascular events, and osteoporosis, are also being recognized.
However, the changing face of AIDS is not a global phenomenon;
paradoxically, the populations that need it the most are the ones with poor
access to HAART.
Whom to Test for HIV Infection

HIV testing should be offered to all persons reporting any of the known
risk factors for HIV acquisition and those requesting a HIV test on their
own, irrespective of their risk behavior. Patients presenting with OIs and
noninfectious illnesses possibly related to HIV, such as lymphoma,
cervical cancer, and anal cancer, should also be tested for HIV infection.
Subtle clinical clues of immunocompromise, such as oral thrush, herpes
zoster in a young person, or failure to thrive in children, should alert the
physician to the possibility of HIV infection. In developing nations, it is
not uncommon for a young child to be the index case of an HIV-infected
family. All women who are receiving antenatal care and, in underdeveloped nations, antenatal cases coming into contact with the health care
system for the first time while in labor, should be screened for HIV
infection. In addition, patients seen in certain high-risk settings in which
the prevalence of HIV infection is known to be high, such as sexually
transmitted disease clinics, tuberculosis clinics, detoxification clinics, and
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correctional facilities, should also be offered HIV testing. HIV infection

should be systematically excluded by testing while evaluating patients
presenting with fever of unknown origin, autoimmune disorders such as
Sjgrens syndrome, systemic lupus erythematosus, Reiters syndrome,
and polymyositis, and neurologic illnesses such as young-onset dementia
and unexplained peripheral neuropathy. To say there are no contraindications for offering HIV testing to a patient is no overstatement.
It is estimated that every fourth HIV-infected person in the United
States is not aware of his or her serostatus. This not only jeopardizes their
own care but also places others at risk of potential transmission, which
could be prevented if they are detected early. In recent times, the current
trend of HIV exceptionalism has come under considerable criticism.
This calls for a public health approach, based on standard principles of
epidemic control, which encompasses a nonselective HIV testing strategy
instead of the targeted-testing practices in vogue. Recent evidence
suggests that nonselective HIV testing, in health care settings and
possibly in the general population also, could be cost effective.
Diagnosis of HIV Infection

All persons who are offered HIV testing should receive appropriate
pretest counseling, and their explicit consent must be obtained. Notification of the result must be confidential and has to be accompanied by
post-test counseling. Post-test counseling should focus on behavior
modification for persons who test negative and for persons who test
positive as well.
Laboratory diagnosis of HIV infection is based on a sequential testing
strategy for the detection of antibodies to HIV-specific antigens. The first
test is a highly sensitive enzyme immunoassay (EIA) that contains
antigens of both HIV-1 and HIV-2. If the test is negative, further testing
is not warranted, unless the exposure was within the past 3 months, in
which case it has to be repeated in 3 months. If the first test returns
positive or indeterminate, the test is repeated in duplicate. If the repeat
EIA tests are positive or indeterminate, the HIV-1 Western blot assay is
needed for confirmation. A Western blot demonstrating antibodies to
products of all three major genes of HIV (gag, pol, and env) is conclusive
evidence of HIV infection (rare false-positives can occur with the
conventional Centers for Disease Control and Prevention criterion that
does not require reactivity to products of pol); a negative assay shows no
bands. Patterns that fall in between are considered indeterminate and must
be repeated after an interval of 1 month. Alternatively, one may proceed
to a specific test such as the p24 antigen capture assay or HIV-1 RNA
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assay. If the HIV-1 Western blot result is discordant with that of EIA, the
possibility of HIV-2 infection should be considered, and HIV-2-specific
testing is warranted.
Four rapid testsOraQuick Advance, Uni-Gold Recombigen, Reveal
G2, and Multispot HIV-1/HIV-2are approved by the U.S. Food and
Drug Administration for point-of-care testing in acute care settings and
for on-site testing at outreach testing sites. A positive result by any of
these tests should be considered only as preliminary positive, and
further confirmatory testing is essential.
Management of the HIV-Infected Patient

Similar to any other disease, there seems to be a learning curve in the
case of HIV care as well. It is well known that the outcome of patients
with HIV/AIDS receiving treatment, at least to a certain extent, depends
on the expertise of the care provider. However, this does not mean that all
HIV-infected patients should be treated only by a specialist, which is not
a feasible proposition. The sheer magnitude of the problem calls for
greater participation on the part of the primary care physician. The U.S.
Department of Health and Human Services panel recommends care by a
physician with at least 20, preferably 50, HIV-infected patients. It is
essential for a primary care physician to be familiar with the initial care
of patients with HIV/AIDS. Primary care physicians who have not cared
for a considerable number of patients with HIV/AIDS should liaise with
a specialist in the field. Referral to a specialist is warranted in cases of
treatment-failure and for the management of complications. Care of
HIV-infected patients is multifaceted, and it needs a multidisciplinary
approach. Such a comprehensive care is delivered better by the primary
care physician.
Initial Evaluation
Evaluation of the HIV-infected patient is carried out in several stages:
assessment of the stage of disease and the need for antiretroviral therapy;
symptom-oriented evaluation for opportunistic conditions; screening to
assess the risk of opportunistic infections (OIs) in the future; screening for
diseases that are co-transmitted, such as sexually transmitted infections
and viral hepatitis; and prevention of further transmission of HIV
infection.
History should be elicited with reference to the route and time of HIV
acquisition. Time of exposure and earlier negative HIV tests are useful to
assess reasonably the latter but may not be available in every case. More
often than not, patients have multiple risk factors, and some patients may
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not report any of the known risk factors. A nonjudgmental approach is

important while taking a sexual history. In addition, questions should
focus on symptoms of other sexually transmitted infections, such as
urethral/vaginal discharge, genital ulcers, dysuria, dyspareunia in females, and perianal/oral ulcers and sore throat in those who report
anal/oral sex. It is also important to elicit how the patient is coping with
the diagnosis of HIV infection and the social and family support available
to the patient. All patients have to be screened for depression and the
presence of suicidal ideations, and they should be encouraged to inform
their spouse/sexual partner of their HIV status. The physician has to be
aware of the legal obligations regarding partner notification because they
vary from place to place.
History should focus also on symptoms such as unexplained weight
loss, prolonged fever, chronic diarrhea, recurrent oral ulcers, dysphagia,
shortness of breath, cognitive decline, and new-onset seizures pointing
toward the presence of opportunistic conditions that need further diagnostic evaluation. In treatment-experienced patients, details of previous
antiretroviral treatment and the response to it should be meticulously
looked into and properly recorded. This can be invaluable while changing
the therapy in cases of treatment failure. Medication history should
include details of allergic reaction to drugs such as cotrimoxazole
(Bactrim), nevirapine (Viramune), and abacavir (Ziagen), and details of
other drug-related adverse effects, such as pancreatitis, peripheral neuropathy, and hepatitis too. Details of past illnesses like tuberculosis and
viral hepatitis, contact with cases of tuberculosis, and travel to areas
endemic for certain infections such as histoplasmosis (Ohio and Mississippi river valleys), coccidioidomycosis (southwestern United States,
northern Mexico), penicilliosis (Southeast Asia), and leishmaniasis (tropics, subtropics, and southern Europe) should be elicited.
A complete physical examination has to be performed at the time of
initial evaluation and at subsequent visits. Attention should be paid to the
presence of lymphadenopathy, hepatomegaly/splenomegaly, serosal effusions, and features of wasting or lipodystrophy. Examination of the
nervous system should focus on possible peripheral neuropathy, proximal
myopathy, focal neurologic signs, meningism, and cognitive impairment.
If the latter is suspected, further neuropsychological testing is required. In
patients presenting with OIs, skin lesions often hold the clue. Funduscopic examination should be done, and in patients with CD4 less than
50 cells/mL, detailed examination by an ophthalmologist is needed to
screen for cytomegalovirus (CMV) retinitis and other ocular manifestations of HIV. One should look for thrush, hairy leukoplakia, mucosal
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lesions of Kaposis sarcoma, and aphthous ulcerations while examining

the oral cavity. Diligent examination of the anogenital area for urethral
discharge, genital/perianal ulcerations, condylomata, and adnexal tenderness in females is needed. Table 3 describes the laboratory evaluation of
HIV-infected patients.
Antiretroviral Therapy
Antiretroviral drugs fall into four classes: nucleoside/nucleotide
reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion
inhibitors (Table 4). HAART is a combination of at least three potent
antiretroviral drugs, typically a combination of two NRTIs as the
backbone, along with either a PI or an NNRTI. Antiretroviral drugs act
by inhibiting the enzyme reverse transcriptase either competitively
(NRTIs) or noncompetitively (NNRTIs) or by inhibiting the viral
protease that is essential for virion assembly (PIs), or by causing
functional inhibition of gp41 that is important for entry into the host
cell (fusion inhibitors). NNRTIs are specific for the HIV-1 reverse
transcriptase and have no activity against HIV-2. HIV-2 carries,
constitutively, many of the mutations associated with PI resistance
that might limit the activity of PIs against HIV-2.
The goal of treatment is to achieve maximal and sustained suppression of plasma viremia to undetectable levels (less than 50 to 80
copies/mL for currently available tests). In this regard, HAART is far
superior to dual and monotherapies and is the standard of care. Table
5 presents the regimens recommended currently for use in treatmentnave HIV-1-infected patients. Selection among these regimens is
made individually, taking into consideration factors such as pill
burden, co-morbidities, potential drug interactions, and pregnancy.
Triple NRTI regimens are inferior to PI- and NNRTI-based regimens
in achieving durable viral suppression, and hence triple NRTI regimens are to be used only when PI/NNRTI-based regimens cannot be
given. NNRTI-based regimens containing nevirapine (Viramune)
should be avoided in females with CD4 more than 250 cells/mL and
in males with CD4 more than 400 cells/mL because of the high risk
of serious hepatotoxicity. Efavirenz (Sustiva) is the preferred NNRTI
in such situations. Efavirenz-based regimens are equivalent to PIbased regimens in terms of efficacy and durability and have the
advantage of low pill burden and limited long-term toxicity. Once
initiated, for reasons mentioned earlier, HAART has to be continued
lifelong. Structured treatment interruptions, aimed at preventing drug
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TABLE 3. Initial and Subsequent Laboratory Evaluation of the HIV-Infected Patient

Baseline Testing
b
CD4 count
Plasma HIV RNA loadc
Viral resistance testingd
Complete blood count
Blood urea, creatinine, electrolytes
Transaminases, alkaline phosphatase,
bilirubin, albumin
Fasting blood glucose
Fasting serum lipids
Urinalysisproteinuria, sediments
Chest radiograph
Electrocardiogram
Serologic Screening
Antitoxoplasma IgGe
Syphilis serology (VDRL or RPR)
Anticytomegalovirus IgGg
HBsAg, HBsAb, HCV-Ab, HAV-Abh
Antivaricella IgGi
Tuberculin skin testj
Urine-based (first-void) NAAT for Chlamydia
species, Neisseria gonorrhoeaek
In Women
Cervical Papanicolaou smear
Vaginal secretions for Trichomonas species
Cervical specimen for NAAT for Chlamydia
species (if sexually active)
Follow-up Testinga
Once in 36 mo
Once in 34 mo if not on treatment; at 28 wk after
initiating/changing treatment, then q34mo
Recommended in virologic failure
q3mo, especially in patients taking zidovudine (Retrovir)
q36mo, especially in patients taking indinavir (Crixivan)
or other nephrotoxic drugs
q2wk in first month, monthly for next 3 mo, then once in
3 mo
If on PIs, at 13 mo after initiation, then q36mo
If on PIs, at 36 mo, then annually
q36mo, especially in patients taking indinavir (Crixivan)
As clinically indicated
If seronegative, when CD4 100/L and unable to
take cotrimoxazole (Bactrim)
Annually, if sexually activef
Not indicated
Not indicated

Abbreviations: HAV-Ab hepatitis A antibody; HBsAb hepatitis B surface antibody; HBsAg hepatitis B
surface antigen; HCV-Ab hepatitis C antibody; NAAT nucleic acid amplification test; PI protease
inhibitor; RPR rapid plasma reagin test; VDRL venereal diseases research laboratory test.
a
May be repeated more frequently if clinically indicated.

Preferably 2 baseline values measured 1 4 wk apart; if discordant, repeat third time.
c
Preferably 2 baseline values measured 1 4 wk apart.
d
Optional in acute HIV infection and before starting treatment in chronic HIV infection.
e
Seronegative patients should be counseled regarding proper preparation of meat and appropriate handling
of cat feces.
f
q3 6mo in asymptomatic persons at higher risk.
g
Seronegative patients should be transfused CMV-negative or leukocyte-depleted blood products only.
h
Vaccination recommended for hepatitis B and hepatitis A, if found susceptible; testing for antibody to
hepatitis B core antigen is optional.
i
May be tested if no history of chickenpox or shingles; if seronegative, postexposure prophylaxis with
varicella zoster immune globulin is indicated.
j
Unless a history of tuberculosis or positive test earlier.
k
In men and women reporting receptive anal sex, culture rectal sample for Chlamydia species, and N.
gonorrhoeae, and in those reporting receptive oral sex, culture pharyngeal sample for N. gonorrhoeae.
b
resistance, place the patient unduly at risk of disease progression and

death during the period of interruption and are not recommended.
Similarly, the strategy of withholding HAART once CD4 counts
improve following treatment (CD4-guided therapy) is also inferior
to uninterrupted treatment.
DM, March 2008
173
TABLE 4. Currently Approved Antiretroviral Drugs

Drug
Dosage
Food/Fasting
Requirement
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Abacavir (Ziagen)
300 mg bid or 600 mg qd
No effect of meals
Didanosine (Videx)
400 mg qd or 200 mg bid (60 kg);
250 mg qd or 125 mg bid
1/2 hr before or 2 hr
(60 kg)
after meals
Emtricitabine (Emtriva)
200 mg qd
No effect of meals
Lamivudine (Epivir)
150 mg bid or 300 mg qd
No effect of meals
Stavudine (Zerit)
40 mg bid (60 kg); 30 mg bid (60
No effect of meals
kg)
Tenofovir (Viread)
300 mg qd
No effect of meals
Zalcitabine (Hivid)
0.75 mg tid
No effect of meals
Zidovudine (Retrovir)
300 mg bid or 200 mg tid
No effect of meals
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Delavirdine (Rescriptor)
400 mg tid
No effect of meals
Efavirenz (Sustiva)
600 mg qd
At or before bedtime;
empty stomach
Nevirapine (Viramune)
200 mg qd for 14 d; then 200 mg
No effect of meals
bid
Protease Inhibitors (PIs)
Amprenavir (Agenerase)
No effect of meals;
1400 mg bid
avoid high-fat mealsa
Atazanavir (Reyataz)
400 mg qd
With mealb
Fosamprenavir (Lexiva)
1400 mg bid; 1400/rtv 200 mg qdc
No effect of meals
Indinavir (Crixivan)/rtv
800/100200 mg q12hd
No effect of meals; if
given unboosted, 1
hr before or 2 hr
after meals
Lopinavir/rtv (Kaletra)
400/100 mg bid or 800/200 mg qde
With meals
Nelfinavir (Viracept)
1250 mg bid or 750 mg tidf
With meal or snack
Ritonavir (Norvir)
100400 mg/dg
With meals
Saquinavir hard gel
1000/100 mg bid
Within 2 hr of meals
(Invirase)/rtv
Saquinavir soft gel
1000/100 mg bid
With or up to 2 hr after
(Fortovase)/rtv
meals
Tipranavir (Aptivus)/rtv
500/200 mg bid
With meals
Fusion Inhibitor
Enfuvirtide (Fuzeon)
90 mg SC bid
Injectable only
Note: Fixed-dose combinations of various NRTIs with or without an NNRTI are also commercially available.
Abbreviations: rtv ritonavir-boosted; SC subcutaneous.
a
Ritonavir, if given for boosting, should not be administered simultaneously.

Not to be taken with antacids.
c
Should be given only as 2 equally divided doses in PI-experienced patients.
d
800 mg q8h if given unboosted.
e
533/133 mg bid in patients taking nevirapine or efavirenz.
f
In pregnant patients, 750 mg tid should not be used.
g
Doses given for pharmacokinetic boosting.
b
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DM, March 2008
TABLE 5. First-Line Antiretroviral Regimens for Treatment-Nave HIV-1-Infected Patients

Recommendation/
Regimen Class
NNRTI-based
PI-based
NNRTI-based
PI-based
Triple NRTI
Antiretroviral Regimen
Preferred
Efavirenz (Sustiva)* (lamivudine [Epivir] or emtricitabine [Emtriva])
(zidovudine [Retrovir] or tenofovir [Viread])
(Lopinavir rtv [Kaletra]) (lamivudine [Epivir] or emtricitabine
[Emtriva]) zidovudine (Retrovir)
Alternative
Efavirenz (Sustiva)a (lamivudine [Epivir] or emtricitabine [Emtriva])
(abacavir [Ziagen] or didanosine [Videx] or stavudine [Zerit])
Nevirapine (Viramune) (lamivudine [Epivir] or emtricitabine
[Emtriva]) (zidovudine [Retrovir] or stavudine [Zerit] or didanosine
[Videx] or abacavir [Ziagen] or tenofovir [Viread])
Atazanavir (Reyataz) (lamivudine [Epivir] or emtricitabine [Emtriva])
(zidovudine [Retrovir] or stavudine [Zerit] or didanosine [Videx] or
abacavir [Ziagen] or tenofovir [Viread] rtv])
(Fosamprenavir [Lexiva] rtv) (lamivudine [Epivir] or emtricitabine
[Videx] or abacavir [Ziagen] or tenofovir [Viread])
(Indinavir [Crixivan] rtv or lopinavir rtv [Kaletra] or saquinavir
[Invirase/Fortovase] rtv) (lamivudine [Epivir] or emtricitabine
[Videx] or abacavir [Ziagen] or teno fovir [Viread])
Nelfinavir (Viracept) (lamivudine [Epivir] or emtricitabine [Emtriva])
(zidovudine [Retrovir] or stavudine [Zerit] or didanosine [Videx] or
abacavir [Ziagen] or tenofovir [Viread])
Abacavir (Ziagen) zidovudine (Retrovir) lamivudine (Epivir)
Note: Once-daily regimens can be tailored by selecting the appropriate drug among the
interchangeable choices presented here.
Abbreviations: NNRTI non-nucleoside reverse transcriptase inhibitor; NRTI nucleoside
reverse transcriptase inhibitor; PI protease inhibitor; rtv low-dose ritonavir (Norvir),
100 400 mg/d for pharmacokinetic boosting; not considered as fourth drug in the regimen;
ritonavir (Norvir) alone should not be used as the sole PI.
Based on Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents, U.S. Department of Health and Human Services, October 2005.
*Contraindicated in women who are pregnant, plan to conceive, or are not using effective
contraception.
Avoid in women with CD4 250/L and men with CD4 400/L (see text).
If combined with tenofovir (Viread), atazanavir (Reyataz) should be boosted with rtv.
Should be used only if NNRTI-based and PI-based regimens should not or cannot be given
(see text).
When to Initiate HAART?

The decision to start HAART is a fine balance between the potential
benefits of delaying the treatment and the risk of progression to AIDS and
death. The patient has to be fully apprised of the benefits as well as the
risks involved, and he or she has to play an active role in decisionDM, March 2008
175
making. Initiation of HAART is warranted in patients with history of any

of the AIDS-defining illnesses (irrespective of CD4 count and viral
load) and in those with advanced immunosuppression (CD4 less than
200 cells/L, irrespective of viral load and symptoms). Conversely,
initiation of HAART can be delayed safely in patients with CD4 counts
more than 350 cells/L and plasma viral load less than 100,000
copies/mL. Data from randomized, controlled trials are lacking regarding
the optimal time of initiating HAART in patients with CD4 counts of
200 to 350 cells/L. Observational data suggest that it is desirable to
initiate HAART in these patients before their CD4 counts drop below
200 cells/L. Current consensus is that these patients should be offered
treatment, especially if the viral load is more than 50,000 to 100,000
copies/mL or the decline in CD4 count is rapid (more than 100 cells/L
per year). Treatment of patients having CD4 more than 350 cells/L
with high viral loads (more than 100,000 copies/mL) is considered
optional, and if treatment is deferred, CD4 count and viral load should
be monitored closely (every 3 months). Likewise, in the absence of
supporting evidence, treatment of patients with acute HIV infection and
those in whom seroconversion occurred within the past 6 months is
considered optional.
Monitoring Response to Antiretroviral Therapy

In a patient on treatment, CD4 counts have to be monitored every 3
to 6 months and the viral load every 3 to 4 months. A reproducible change
in absolute CD4 count of at least 30% and/or 3 percentage point change
in the CD4 percentage are considered significant. Similarly, for viral
load, a threefold or 0.5 log10 copies/mL change is deemed significant. It
is important that these estimations are not performed during an episode of
intercurrent infection or vaccination because transient fluctuations in
viremia and CD4 counts can occur during such episodes. Because of
large variations in absolute CD4 count estimations and interassay
differences in estimating viral load, serial evaluations should be obtained
from the same laboratory using the same assay. Before making any
treatment change based on the laboratory results, they should be repeated
and reconfirmed.
Following the initiation of effective antiretroviral therapy, CD4
counts rapidly improve within a few weeks, largely as a result of
redistribution of cells, and they subsequently improve at the rate of
approximately 100 cells/L per year over the subsequent years until a
plateau is reached. Plasma viral load rapidly falls in the initial weeks and
becomes undetectable in approximately 4 to 6 months. The rate of initial
176
DM, March 2008
decline in viral load depends on the potency of the HAART regimen, and
it predicts the durability of viral suppression. Determination of viral load
at 2 to 8 weeks after the initiation or change in treatment thus is also
recommended. An adequate response is defined as a decrease of at least
1.0 log10 copies/mL at 2 to 8 weeks after starting treatment; plasma viral
load should become undetectable by 16 to 24 weeks.
Drug Resistance and Resistance Testing

A patient may be infected with a drug-resistant virus to begin with
(primary resistance) or else resistance can emerge as a result of treatment
(secondary). The latter is more common. With widespread use of
antiretrovirals, primary resistance is increasing. Most NNRTI-associated
resistance mutations confer cross-resistance to all other NNRTIs as well.
Among NRTIs, cross-resistance is common but varies by drug. Paradoxically, lamivudine (Epivir) resistance related to the M184V mutation
enhances the susceptibility to zidovudine (Retrovir). With PIs, initial
mutations might confer limited resistance only; however, accumulation of
sequential mutations leads to broad cross-resistance. Tipranavir (Aptivus)/ritonavir (Norvir) is active against such strains of HIV-1 resistant to
multiple PIs.
Drug-resistance testing is done by either genotypic or phenotypic
assays. Overall, the resistance tests have a limited sensitivity. Resistance
may not be detected if viremia is less than 1000 copies/mL or the
frequency of resistant quasispecies is less than 10% to 20%. These tests
are to be performed while the patient is still taking the failing regimen or
within 4 weeks after discontinuation to avoid overgrowth of the resistant
quasispecies by the wild strain. The exact role of resistance testing in
clinical practice is not yet clear. In patients receiving tailored regimens
based on resistance testing, benefit in terms of improved virologic
outcome is modest only. However, testing for drug resistance is indicated
in patients failing treatment, those having suboptimal virologic response,
and in those treated for acute HIV infection. Routine resistance testing in
drug-nave patients with chronic HIV infection may also be considered,
especially if the prevalence of primary resistance is more than 4%. Failure
to identify any resistance in a patient failing treatment points toward poor
adherence.
Treatment Failure
Failure of treatment can be classified into virologic failure, immunologic failure, and clinical progression. Virologic failure is evidenced by
repeated detection of viremia more than 400 copies/mL after 24 weeks or
DM, March 2008
177
more than 50 copies/mL after 48 weeks of treatment in a drug-nave

patient or by persistent viremia after achieving complete suppression
(virologic rebound). Inadequate CD4 response (improvement of fewer
than 25 to 50 cells/L in the first year) or a fall below the pretreatment
CD4 level constitutes immunologic failure. Occurrence or recurrence of
HIV-related events after the third month of HAART, in the absence of an
alternative explanation, is considered indicative of clinical progression.
Usually virologic failure is the first to occur, to be followed months to
years later by immunologic failure, and finally by clinical progression.
Sometimes discordant responses (i.e., immunologic failure and clinical
progression despite suppressed viremia) may occur. Provided that viremia
is well suppressed, changing the regimen may not be warranted in such
settings.
In a patient with virologic failure, although drug resistance is the
proximate cause of failure, one must carefully look for factors that
contributed to the emergence of drug resistance in that particular patient
and try to address them. Otherwise, the new regimen is also bound to fail.
Such factors include inadequate regimen potency, high baseline viral
load, poor adherence, drug intolerance, preexisting resistance, and suboptimal pharmacokinetics because of malabsorption, noncompliance with
food/fasting requirements, and drug interactions. Past-treatment experience of the patient should also be evaluated to inform them about further
treatment choices (Table 6). In general, the new regimen should include
at least two, preferably three, fully active drugs. A fully active drug is one
that is likely to be effective based on both the treatment history and
susceptibility on resistance testing. Addition of a single drug may be
justified if substitution is being made to manage toxicity in a patient with
otherwise good response or in a patient failing treatment where no
resistance is identified, after ruling out poor adherence and improperly
timed resistance testing. Although the goal of treatment remains complete
suppression of viremia below detectable limits, in treatment-experienced
patients with resistance to multiple drugs, this may not always be feasible.
In such patients with limited options, even a 0.5 to 1.0 log10 reduction in
viral load may be acceptable. In patients failing treatment with extensive
prior treatment, if no fully active drug is available, continuing with the
failing regimen might decrease the risk of clinical progression.
Adherence to Treatment
Adherence to prescribed treatment is a complex issue but of utmost
importance. Antiretroviral treatment is very exacting in terms of adherence when compared with other chronic diseases; missing as little as 5%
178
DM, March 2008
TABLE 6. Salvage Therapy in Patients with Treatment Failure (Virologic Failure)

First virologic failure
Initial Regimen
Resistance Identified
NNRTI-based
(2 NRTIs
NNRTI)
2 NRTIs (based on resistance

testing) PI (unboosted or
rtv-boosted)
PI-based (2
NRTIs PI
[unboosted
or rtvboosted])

testing) NNRTI or 2
NRTIs (based on resistance
testing) a new boosted
PI (based on resistance
testing) or 1 or more
NRTI(s) (based on
resistance testing)
NNRTI a new boosted PI
(based on resistance
testing)
Triple NRTI (3
NRTIs)

testing) NNRTI or PI
(unboosted or rtv-boosted)
or 1 or more NRTI(s)
(based on resistance
testing) NNRTI PI
(unboosted or rtv-boosted)
or NNRTI PI (unboosted
or rtv-boosted)
No Resistance
Identified
Check adherence to
treatment; if
poor, address
compliance. Was
the resistance
testing properly
timed? (see text);
if not properly
timed, continue
same regimen;
repeat genotypic
testing in 24 wk
or start a new
regimen; repeat
genotypic testing
in 24 wk. If
adherence and
timing of testing
are acceptable,
start a new
regimen; repeat
genotypic testing
in 24 wk or
intensify by
adding 1 NRTI
(tenofovir
[Viread]) or boost
the PI with rtv.
Subsequent Virologic
Failures
Include at least 2,
preferably 3, fully
active drugs (see
text); add a drug
from new class, if
available. If 3-class
virologic failure,
start 1 NRTI
(based on
resistance testing)
a new boostedPI (based on
resistance testing)
enfuvirtide
(Fuzeon). If only 1
fully active agent
available, add to
failing regimen only
if CD4 100/L;
otherwise, continue
failing regimen. If
no fully active
agent available,
continue failing
regimen; do not
interrupt.
Based on Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, U.S.
Department of Health and Human Services, October 2005.
Abbreviations: NNRTI non-nucleoside reverse transcriptase inhibitor, NRTI nucleoside reverse
transcriptase inhibitor, PI protease inhibitor, rtv ritonavir (Norvir).
to 10% of doses is known to affect virologic outcome adversely. The

natural tendency is to miss a few doses, and physician estimates of
adherence are known to be unreliable. It is thus important to suspect
noncompliance in every patient. Before initiating treatment, the patient
must be counseled regarding medication requirements, and readiness to
take the treatment has to be ensured. It has to be impressed on the patient
that the first regimen has the best chance for long-term success. AdherDM, March 2008
179
ence counseling and assessment of adherence should be done at each

clinical encounter. Adherence is conventionally assessed by patient
self-reports, pill counting, and a patient-recorded medication diary.
Microelectronic monitoring systems like Medication Event Monitoring
System (MEMS Track Cap) and therapeutic drug monitoring could
provide more objective assessment of adherence. However, all these
methods have their limitations, and it is preferable to use more than one
method simultaneously.
Noncompliance with treatment has many causes. Patient-related factors,
such as substance abuse, depression, lack of social support, and age;
medication-related factors, such as dosing frequency, pill burden, food/
fasting requirements, and adverse effects; and health care system-related
factors, such as attitude of staff, communication, and accessibility, all
operate in tandem to influence the adherence. Adherence can be improved
by simplifying the dosage schedules, providing pillboxes, tailoring to suit
the lifestyle, entrusting medication intake to a family member, using
reminder calls and alarms and community-based case managers, alerting
to adverse effects, providing patient education materials, making the
clinic appointments convenient, and making the health system encounter
pleasant. In patients found nonadherent, enough time should be spent to
identify the responsible factors and to find acceptable solutions while
involving the patient actively in the process.
Adverse Drug Reactions and Drug Interactions

Adverse drug reactions (ADRs) are common with antiretroviral therapy
and an important cause of nonadherence. They also contribute to a
significant proportion of clinic visits and mortality. ADRs can be
idiosyncratic, dose-related, time-related (delayed), or dose- and timerelated (cumulative). A particular ADR may be common to all drugs of
the same class (e.g., lactic acidosis and fatty liver because of NRTIs,
lipodystrophy because of PIs), or it might be drug specific (e.g.,
hypersensitivity to abacavir [Ziagen], nephrolithiasis because of indinavir
[Crixivan]). The patient often is on other drugs as well, with overlapping
ADR profiles, apart from antiretrovirals. A symptom-based approach is
useful from a practical point of view (Table 7). Although many of the
ADRs can be managed conservatively, some, such as symptomatic lactic
acidosis, systemic hypersensitivity reactions, StevensJohnson syndrome,
acute pancreatitis, and severe hepatotoxicity, are potentially life threatening. Serious ADRs necessitate withdrawal of the offending drug, and
rechallenge of the drug should not be attempted in these situations.
Drug interactions are often the underlying cause of ADRs. PIs are
180
DM, March 2008
TABLE 7. Approach to Adverse Drug Reactions in the HIV-Infected Patienta

Causative Drug(s)
Adverse Effect
Manifestations
Stepwise Action
Antiretroviral(s)
Stevens-Johnson
syndrome/
toxic
epidermal
necrolysisb
Rash, mucosal
ulcerations, fever,
hepatic dysfunction
NNRTIs most
commonly
NVP; rarely
APV, LPV/r,
ATV, ABC,
ZDV, ddI
Hypersensitivity
reactionc
Fever, diffuse rash,

malaise, arthralgia,
respiratory and GI
symptoms,
circulatory collapse
ABC, enfuvirtide
(Fuzeon)
Skin rash
Maculopapular rash
only; no blisters,
skin tenderness,
mucosal ulceration,
or fever
DLV EFV
APV, fAPV
ATV NVP
ABC, TPVd
GI intolerancee
Anorexia, nausea,
vomiting, epigastric
pain
PIs, ddI, ZDV
Diarrhea
Pis, especially
NFV, LPV/r,
and buffered
ddI
formulations
Jaundice, fever,
vomiting, hepatic
necrosis,
encephalopathy
NVP
Symptomatic or
subclinical hepatic
enzyme elevations
NNRTIs, d4T,
ddI, ZDV, Pis,
especially
TPV
Hepatotoxicityf
DM, March 2008
Other Drugs
Discontinue all ARVs
and any other
possible drug;
manage like
severe burns; do
not rechallenge
offending drug.
Cotrimoxazole,
sulfadiazine,
and any other
dapsone
possible drug; rule
out other causes;
do not rechallenge
ABC/enfuvirtide.
Antihistamines;
Cotrimoxazole,
continue offending
sulfadiazine,
drug; watch for
dapsone,
progression of
atovaquone,
rash; if so,
voriconazole
discontinue.
Isoniazid,
Administer with food
rifamycins,
(not for ddI,
pyrazinamide
unboosted IDV);
antiemetics;
switch to less
emetogenic ARV.
Clindamycin,
Rule out OIs;
atovaquone
antimotility
agents, calcium
salts, bulk forming
agents;
rehydration, if
needed.
Isoniazid,
rifamycins,
and any other
pyrazinamide
possible drug; rule
out viral hepatitis;
supportive
management; do
not rechallenge
NVP.
If symptomatic,
Isoniazid,
discontinue all
rifamycins,
ARVs and switch
pyrazinamide,
to nonhepato toxic
azithromycin,
ARVs after
clarithromycin,
normalization; if
all azole
asymptomatic,
antifungals
monitor closely.
Cotrimoxazole,
sulfadiazine,
dapsone,
atovaquone,
voriconazole
181
TABLE 7. Continued
Causative Drug(s)
Adverse Effect
Manifestations
Stepwise Action
Antiretroviral(s)
Lactic acidosis,
fatty liverg
Nonspecific GI
symptoms,
tachypnea,
tachycardia,
hepatomegaly,
hyperlactatemia,
multiorgan failure
NRTIs
especially
d4T, ddI, ZDV
Epigastric painpostprandial,
vomiting, fever,
elevated amylase,
lipase
ddI, d4T, ddC,

RTV; 3TC (in
children)
Numbness,
paresthesiaoften
painful; recovery
possibly
incomplete
ddI, d4T, ddC
Myalgia, muscle
tenderness,
proximal
weakness,
elevated creatine
kinase
ZDV
Flank pain,
nondescript
abdominal pain,
dysuria, hematuria,
renal dysfunction
IDV
Renal dysfunction;
nephrogenic
diabetes insipidus;
Fanconi syndrome
IDV, TDF
Pancreatitisg
Peripheral
neuropathyg
Myopathyg
Nephrolithiasis,
crystalluriah
Nephrotoxicity
Other Drugs
Discontinue all
ARVs; hydration;
supportive
treatment; IV
thiamine/riboflavin;
switch to ABC/
3TC/TDF or NRTIsparing regimens.
Metformin
Discontinue
offending drugs;
manage like acute
pancreatitis
related to any
Alcohol,
other cause; do
cotrimoxazole,
not rechallenge.
pentamidine
Switch to ABC/3TC/
TDF; gabapentin,
tricyclic
antidepressants,
narcotic
analgesics.
Isoniazid
Switch to another
NRTI; improves in
34 wk after
discontinuation;
coenzyme-Q, LStatins,
carnitine
fibrates,
(unproven).
steroids
Discontinue IDV;
hydration and
analgesics; IDV
can be resumed
with plenty of oral
fluids; if recurs,
Cotrimoxazole,
consider
sulfadiazine,
switching.
acyclovir
Discontinue
Acyclovir,
offending drug;
amphotericin
hydration;
B,
generally
cotrimoxazole,
reversible.
pentamidine
metabolized by the hepatic cytochrome P450 (CYP) enzymes. At the

same time, PIs are potent inhibitors of CYP. Conversely, NNRTIs,
especially efavirenz (Sustiva), are a potent inducer of CYP. When
antiretrovirals are co-administered with other drugs metabolized by or
affecting CYP (antihistamines, prokinetics, lipid-lowering agents, antifungals, antitubercular drugs, anticonvulsants, etc.), complex pharmacokinetic interactions occur; this can lead to potentially toxic or subthera182
DM, March 2008
TABLE 7. Continued
Causative Drug(s)
Adverse Effect
Manifestations
Stepwise Action
Antiretroviral(s)
Hematologic
CNS symptomsj
Anemia, neutropeniai
ZDV
Bleeding tendency in
hemophiliacs
Pis
Eosinophilia
Enfuvirtide
(Fuzeon)
Drowsiness,
insomnia, vivid
dreams,
nightmares,
hallucination,
worsening of
psychiatric
disorders, suicidal
ideation
EFV
Other Drugs
Discontinue
Cotrimoxazole,
concomitant
dapsone,
marrow
sulfadiazine,
pyrimethamine, suppressant, if
any; exclude
flucytosine,
marrow
trimetrexate,
involvement by
amphotericin
OIs/malignancy;
B,
erythropoietin or
ganciclovir,
filgrastim; switch
valganciclovir,
to another NRTI.
rifabutin
Factor VIII infusion;
consider NNRTIbased regimens.
Exclude
Cotrimoxazole,
disseminated
dapsone,
sulfadiazine
strongyloidiasis,
malignancy; watch
for
hypersensitivity.
Isoniazid,
Usually resolve in
dapsone,
24 wk; consider
steroids
discontinuation, if
persistent or
exacerbates
psychiatric illness.
peutic drug levels. In a patient on HAART, unnecessary prescriptions are

to be avoided, and it is prudent always to check the compatibility and the
dose modifications needed before prescribing.
Management of Opportunistic Conditions

General Considerations
OIs are the most common cause of disability and death in HIV-infected
patients who are not receiving treatment. Hence, it is important that OIs
are promptly recognized and treated. Different pathogens may cause
similar disease patterns, and multiple OIs may occur concurrently.
Although it is important to make a definitive diagnosis in these patients,
diagnostic work-up should not delay unduly the initiation of appropriate
treatment. Empirical treatment based on clinical suspicion may be
DM, March 2008
183
TABLE 7. Continued
Causative Drug(s)
Adverse Effect
Manifestations
Stepwise Action
Antiretroviral(s)
Lipodystrophy
Loss of
subcutaneous fat,
buffalo hump,
double chin,
dyslipidemia,
insulin resistance,
diabetes mellitus
PIs (except
ATV); NRTIs,
especially
d4T
Other Drugs
Steroids
Assess cardiac risk

factors; lifestyle
modification;
metformin,
glitazones,
statins, fibratesk;
consider early
switching to ATVor NNRTI-based
regimens.
Abbreviations: 3TC lamivudine (Epivir); ABC abacavir (Ziagen); APV amprenavir (Agenerase); ATV
atazanavir (Reyataz); CNS central nervous system; d4T stavudine (Zerit); ddC zalcitabine (Hivid); ddI
didanosine (Videx); DLV delavirdine (Rescriptor); EFV efavirenz (Sustiva); fAPV fosamprenavir
(Lexiva); FTC emtricitabine (Emtriva); GI gastrointestinal; IDV indinavir (Crixivan); LPV/r
lopinavir/ritonavir (Kaletra); NFV nelfinavir (Viracept); NNRTI non-nucleoside reverse transcriptase
inhibitor; NRTI nucleoside reverse transcriptase inhibitor; NVP nevirapine (Viramune), OI opportunistic infection; PI protease inhibitor; RTV ritonavir (Norvir); TDF tenofovir (Viread); TPV tipranavir
(Aptivus); ZDV zidovudine (Retrovir).
Based on Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, U.S.
Department of Health and Human Services, October 2005.
a
Only common and serious side effects are dealt with; side effects such as osteoporosis, avascular
osteonecrosis (PIs), unconjugated hyperbilirubinemia, retinoid-like effects (IDV) and cranial malformations
(EFV) are also known to occur.
b
Approximately 0.3%1% with NVP; a low dose, lead-in period for NVP (see Table 4) may decrease the risk;
less common (0.1%) with DLV and EFV; occurs in the initial weeks after initiation; safety of replacing NVP
with another NNRTI is unknown.
c
Approximately 5% with ABC; once daily dosing possibly increases the risk; If ABC-related, symptoms resolve
within 48 hrs after discontinuation of ABC.
d
APV, fAPV, and TPV are sulfonamide derivatives; potential cross-hypersensitivity with sulfonamides.
e
Symptoms begin with first doses; might abate with time.
f
Low-dose, lead-in period for NVP might reduce the risk; monitoring: see Table 3; onset within the first few
weeks with NNRTIs, after weeks to months with PIs, and after months to years with NRTIs; discontinuation
of 3TC, FTC, or TDF in HBV co-infected patients might cause acute flare-up of hepatitis; safety of replacing
NVP with another NNRTI is unknown.
g
Class-specific adverse effect of NRTIs, because of mitochondrial toxicity; do not combine ddI/d4T/ddC;
ABC, 3TC, and TDF are less prone; all 4 syndromes can occur in variable combinations; symptomatic lactic
acidosis is rare but is associated with high mortality.
h
Approximately 10% of patients taking IDV experience at least 1 episode of colic; monitoring: see Table 3;
recurrence is seen in only 50%, if fluid intake is improved (at least 1.52 L of noncaffeinated fluid; water
preferably).
i
Almost all ZDV-treated patients have isolated macrocytosis; anemia and neutropenia approximately 1% 4%
and 2% 8% respectively; monitoring: see Table 3
j
Occurs during initial weeks of treatment; patients are to be warned to restrict risky activities.
k
Only atorvastatin (Lipitor) and pravastatin (Pravachol) among statins, and gemfibrozil (Lopid) and
fenofibrate (Triglide) among fibrates, can be co-administered with Pis.
justified in acutely ill patients. In a patient with a severe OI as the initial

manifestation of HIV disease, management of the OI takes precedence
over immediate initiation of HAART. This avoids potential drug interactions and possibly decreases the occurrence of immune reconstitution
184
DM, March 2008
inflammatory syndrome (IRIS). However, in patients with OIs for which

no effective treatment is available (cryptosporidiosis, microsporidiosis,
progressive multifocal leukoencephalopathy, and Kaposis sarcoma),
HAART itself can result in improvement and hence should be initiated as
soon as possible.
IRIS manifests as the occurrence of a new OI or worsening of a
preexisting OI following initiation of HAART, usually in the first 3
months. Symptoms include fever, lymphadenopathy, serosal effusions,
worsening or fresh pulmonary infiltrates, vitreitis, uveitis, and intracranial lesions. Occasionally life-threatening complications like acute
respiratory distress syndrome (ARDS) and acute renal failure develop.
Most instances of IRIS respond well to nonsteroidal anti-inflammatory
drugs. HAART and OI-specific treatment need to be continued without
interruption. Steroids may be useful in patients with life-threatening
complications.
OIs can be prevented by timely initiation of primary chemoprophylaxis
(Table 8). It has to be stressed that OIs listed in the table can also occur,
albeit less often, in patients with CD4 counts above the cutoffs for
initiation of prophylaxis. Following treatment for an episode of OI,
lifelong secondary prophylaxis is needed to prevent relapse. However, if
a sustained improvement in CD4 count is achieved following HAART,
secondary prophylaxis for most of the OIs and primary prophylaxis can
be withdrawn safely. Table 9 presents the possible etiology of opportunistic conditions. Management of common potentially life-threatening
OIs is presented next.
Pneumocystis Jiroveci Pneumonia (PCP)

PCP is the most common OI in HIV-infected patients. Approximately
90% of cases occur among patients with CD4 less than 200 cells/L.
Although the overall mortality is approximately 10% to 20%, it exceeds
50% in those requiring mechanical ventilation for respiratory failure. PCP
manifests as a subacute febrile illness accompanied by nonproductive
cough and progressive exertional dyspnea. In patients with mild disease,
physical findings are often scanty, barring tachypnea and scattered
so-called cellophane crackles. Hypoxemia is useful to assess the severity
of disease, and moderate to severe hypoxemia (PaO2 less than 70 mm Hg
or [A-a]DO2 more than 35 mm Hg while breathing ambient air) indicates
severe disease. Chest radiograph demonstrates diffuse, bilateral, interstitial infiltrates in a perihilar distribution. Atypical radiographic appearances like upper lobe predominance (in patients on inhaled pentamidine
DM, March 2008
185
TABLE 8. Primary Chemoprophylaxis for Opportunistic Infections in the HIV-Infected Patient*,

Opportunistic
Pathogen
Criteria for
Initiation
Pneumocystis jiroveci
CD4 200/
L;
oropharyngeal
candidiasis
TMP-SMX (Bactrim),
960 mg qd or
480 mg qd
Toxoplasma gondii
CD4 100/
L in IgG
toxoplasma
antibodypositive
patients
TMP-SMX (Bactrim),
960 mg qd
Mycobacterium
avium-intracellulare
CD4 50/L
Mycobacterium
tuberculosis
TST 5 mm;
positive TST
in past
without
treatment;
contact with
active case,
irrespective of
TST
Azithromycin
(Zithromax),
1200 mg qw, or
clarithromycin
(Biaxin), 500 mg
bid
Isoniazid (Laniazid)
pyridoxine,
300 50 mg qd
or 900 100
mg biw, for 9 mo
Preferred Regimen
Alternative
Regimens
Criteria for
Discontinuation
TMP-SMX (Bactrim),
960 mg tiw, or
dapsone, 100
mg qd, or
aerosolized
pentamidine
(NebuPent), 300
mg monthly, or
atovaquone
(Mepron), 1500
mg qd
TMP-SMX (Bactrim),
480 mg qd, or
dapsone, 50 mg
qd,
pyrimethamine,
50 mg qw,
leucovorin, 25
mg qw, or
atovaquone
(Mepron), 1500
mg qd
Rifabutin
(Mycobutin), 300
mg qd
CD4 200/L
for 3 mo
Rifampicin
(Rifadin), 600 mg
qd for 4 mo
CD4 200/L
for 3 mo
CD4 100/L
for 3 mo
Not applicable
Abbreviations: biw twice weekly; TMP-SMX cotrimoxazole (Bactrim); TST tuberculin skin test; qw
once a week; tiw 3 times a week.
Based on USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with
HIV, 2001.
*Apart from chemoprophylaxis, annual influenza immunization in all, pneumococcal vaccination in those
with CD4 200/L, and hepatitis A and hepatitis B vaccinations in susceptible patients are recommended.
Primary chemoprophylaxis not recommended for cytomegalovirus, Cryptococcus neoformans, Histoplasma

capsulatum, Coccidioides immitis, Salmonella species, herpes simplex, and Candida species.
Primary prophylaxis to be restarted if CD4 falls again below levels recommended for initiation.
Not prophylaxis in strict sense.
For isoniazid-susceptible M. tuberculosis only; if probability of exposure to isoniazid-resistant M. tuberculosis is high, rifampicin (Rifadin), 600 mg qd, or rifabutin (Mycobutin), 300 mg qd, for 4 mo.
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DM, March 2008
TABLE 9. Etiology of Opportunistic Conditions in the HIV-Infected Patient

System Affected/
Syndrome
Pulmonary
Central nervous
system (CNS)
Gastrointestinal
(GI)
Undifferentiated
fever
Etiology (infectious as well as noninfectious)

Very Common
Somewhat Common
Rare
Nocardia species
Legionella species
Myobacterium avium
complex
Toxoplasma gondii
Cryptosporidium
Rhodococcus equi
Strongyloides
Primary pulmonary
hypertension
DILS
Cryptococcus
Nocardia species
species
Histoplasma species
Toxoplasmosis
Coccidioides immitis
ADRs
Aspergillus species
Psychiatric illness
Listeria monocytogenes
HIV dementia
Varicella-zoster virus
PMLE
Herpes simplex virus
CNS lymphoma
Treponema pallidum
Acanthamoeba species
Trypanosoma cruzi
DILS
Cytomegalovirus
Shigella species
Amebiasis
Clostridium difficile Campylobacter species Strongyloides
Salmonella species Microsporum
GI lymphoma
M. avium complex
Cryptosporidium
Kaposis sarcoma
Giardia lamblia
Isospora
Enteroaggregative
ADRs
Cyclospora
Escherichia coli
DILS
M. avium complex
Cryptococcus species
Extrapulmonary
M. tuberculosis*
Histoplasma species
Pneumocystis
Cytomegalovirus
Endocarditis
Bartonella henselae
ADRs
Lymphoma
Coccidioides immitis
Sinusitis
Mycobacterium
Catheter-related
kansasii
Early PCP
Penicillium marneffei
Acute HIV syndrome
Leishmania species
Toxoplasma gondii
PCP
Streptococcus
pneumoniae
Haemophilus
influenzae
Myobacterium
tuberculosisa
Pseudomonas
aeruginosa
Staphylococcus aureus
Enteric GNB
Histoplasma species
Cryptococcus species
Cytomegalovirus
Kaposis sarcoma
Aspergillus species
Pulmonary lymphoma
Heart failure
M. tuberculosisa
Cytomegalovirus
Bacterial brain abscess
Abbreviations: ADR adverse drug reaction; DILS diffuse infiltrative lymphocytosis

syndrome; GNB gram-negative bacilli; PCP Pneumocystis jiroveci pneumonia; PMLE
progressive multifocal leukoencephalopathy.
Adapted from Sax PE: Opportunistic infections in HIV disease: Down but not out. Infect Dis Clin
North Am 2001;15:433 455.
*Incidence of tuberculosis varies greatly depending on the local prevalence.
DM, March 2008
187
[NebuPent] prophylaxis), nodular infiltrates, cysts, and pneumothorax are

also seen. An apparently normal-looking radiograph in a patient with
compatible clinical presentation does not rule out a diagnosis of PCP.
Diagnosis is established by the demonstration of cysts and trophozoites of
Pneumocystis in induced sputum (sensitivity, 50% to 90%), bronchoalveolar lavage (90% to 99%), and transbronchial lung biopsy (95% to
100%) specimens by Gomori methenamine silver, Giemsa, or calcofluor
staining. Immunofluorescent staining has better sensitivity and specificity
than the tinctorial stains. rRNA-PCR techniques are currently being
evaluated and can be used on oral washings.
Cotrimoxazole (TMP-SMX, Bactrim) is the drug of choice. Mild to
moderately severe cases can be managed with oral TMP-SMX (two
double-strength tablets [Bactrim DS] three times daily for 21 days) on an
ambulatory basis. Patients developing PCP despite TMP-SMX (Bactrim)
prophylaxis can also be effectively treated with standard doses of
TMP-SMX. Intravenous therapy (15-20 [TMP]/75-100 [SMX] mg/kg/day
every 6 to 8 hours for 21 days) is indicated for patients with severe
hypoxemia. In addition, steroids (prednisone,1 40 mg orally twice daily
for days 1 to 5, 40 mg every day for days 6 to 10, and 20 mg every day
for days 11 to 21) improve the mortality and reduce the need for
mechanical ventilation in severe cases and should be started within 72
hours of starting anti-PCP treatment. Lack of clinical improvement or
worsening hypoxemia after at least 4 to 8 days of anti-PCP treatment
indicates failure and warrants changing of treatment. Serious ADRs
related to TMP-SMX (Bactrim) also often necessitate a treatment change.
The preferred alternative treatments are pentamidine (Pentam, 4 mg/kg
intravenously [IV] every day) or clindamycin (Cleocin, 600 to 900 mg IV
every 6 to 8 hours) plus primaquine1 (15 to 30 mg [base] orally every
day). Dapsone (100 mg orally every day) plus trimethoprim (Trimpex,1
15 mg/kg/day orally thrice daily), atovaquone (Mepron, 750 mg orally
twice daily), or trimetrexate (Neutrexin, 1.2 mg/kg IV every day with
leucovorin, 0.5 mg/kg IV every 6 hours) can be used also as alternatives
in mild to moderately severe PCP. Following treatment, patients should
be administered secondary prophylaxis, which has to be discontinued if
the CD4 counts improve to more than 200 cells/L for 3 months after
initiating HAART. However, in those who develop PCP while their
CD4 counts were more than 200 cells/L, it is prudent to continue the
secondary prophylaxis lifelong.
Not FDA approved for this indication.
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DM, March 2008
Cryptococcosis
Cryptococcosis occurs mostly among patients with CD4 less than 50
cells/L. Although the route of infection is via the lungs, most often the
disease manifests as meningitis. Disseminated infection is common in
HIV-infected patients, and in fact approximately 60% of patients with
AIDS-associated cryptococcal meningitis have fungemia. Pulmonary
involvement occurs either as a part of disseminated disease or as primary
pneumonia. Molluscoid skin lesions with central hemorrhagic crust may
be seen. Patients typically present with subacute onset of fever, prominent
headache, and vomiting. The classical signs of meningeal inflammation
are often absent. Occasionally, cognitive decline and personality changes
might be the only presenting symptoms. Cryptococcomas may present as
a focal neurologic deficit.
Diagnosis is readily established by the demonstration of yeast cells by
India ink staining of cerebrospinal fluid (CSF). Fungal culture and latex
agglutination for cryptococcal antigen have better sensitivity than the
India ink stain. The antigen can also be detected in the blood in most
patients with meningitis. Untreated disease is uniformly fatal. Amphotericin B deoxycholate (Fungizone, 0.7 mg/kg IV every day for 2 weeks) is
the preferred treatment. Infusion-related ADRs, such as chills, rigors, and
fever, are common and can be reduced by premedicating with acetaminophen (Tylenol). Liposomal preparations of amphotericin B (AmBisome,
4 mg/kg/day) can be used also to reduce nephrotoxicity. Addition of
flucytosine (Ancobon, 25 mg/kg orally four times a day for 2 weeks)
sterilizes the CSF faster and reduces the rate of relapse but not mortality.
Amphotericin B is to be followed by fluconazole (Diflucan, 400 mg orally
every day) for at least 8 weeks or until the CSF cultures become sterile
and then lifelong (200 mg every day) for secondary prophylaxis. In
patients with immune recovery following HAART, secondary prophylaxis can be discontinued if the CD4 count is more than 100 to 200
cells/L for 6 months. Raised intracranial pressure is very common and
associated with early deaths. If symptomatic, daily lumbar punctures to
reduce the pressure are needed, and in refractory cases, CSF shunting
should be performed.
Disseminated Mycobacterium Avium Infection

Like cryptococcosis and CMV disease, disseminated atypical mycobacterial infections occur more commonly in patients with CD4 less than
50 cells/L. Most infections are caused by Mycobacterium aviumintracellulare. Infections by Mycobacterium kansasii and Mycobacterium
DM, March 2008
189
haemophilum are also known to occur. Symptoms are nonspecific and

include fever, weight loss, diarrhea, and abdominal pain. Peripheral and
axial lymphadenopathy, hepatosplenomegaly, anemia, elevated alkaline
phosphatase, and bone marrow infiltration are common features. Localized manifestations occur commonly as a manifestation of IRIS. Pulmonary lesions in the form of miliary nodules and air-space infiltrates may
be seen. Diagnosis is established by demonstrating mycobacteremia or by
isolating the organism from involved tissue specimens.
Treatment should include at least two effective drugs, usually clarithromycin (Biaxin, 500 mg orally twice daily) and ethambutol (Myambutol,1
15 mg/kg orally every day). Addition of a third drug should be
considered, especially when CD4 is less than 50 cells/L, effective
HAART is unavailable, or the mycobacterial load is high (more than 2.0
log10 colony-forming units/mL of blood). Rifabutin (Mycobutin,1 300 mg
orally every day) is the preferred third drug. Fluoroquinolones and
amikacin (Amikin)1 can be used as alternative agents. Generally, if
possible, HAART should be initiated within 1 to 2 weeks after initiating
antimycobacterial therapy. Lack of clinical improvement accompanied by
persisting mycobacteremia after 4 to 8 weeks of treatment indicates
failure, and further selection of drugs should be guided by susceptibility
testing. Treatment has to be continued lifelong for secondary prophylaxis.
However, if the CD4 count improves to more than 100 cells/L for 6
months, it can be discontinued, provided the patient is asymptomatic and
treatment has been given for at least 12 months.
Cytomegalovirus Disease
Retinitis is the most common manifestation of CMV disease. It presents
as progressive painless loss of vision, and patients often experience
floaters. Funduscopy reveals focal necrotizing retinitis, characterized by
perivascular fluffy infiltrates with hemorrhages. Lesions spread centrifugally from the periphery, and those adjacent to the macula are sight
threatening. Visual loss, if it occurs, is irreversible. Other manifestations
include colitis, esophagitis, meningoencephalitis, and pneumonitis. Colitis causes persistent diarrhea and may result in extensive hemorrhage,
perforation, and bacterial sepsis. CNS disease presents as dementia,
ventriculoencephalitis, or ascending polyradiculomyelopathy. Viremia in
the absence of end-organ disease may be seen but does not warrant
immediate therapy.
Sight-threatening retinitis is treated with an intraocular ganciclovir
1
190
DM, March 2008
implant (Vitrasert) along with valganciclovir (Valcyte, 900 mg orally

every day) lifelong. For peripheral lesions, valganciclovir (Valcyte), 900
mg orally twice daily for 2 to 3 weeks is to be followed by 900 mg every
day for life. Ganciclovir (Cytovene, 5 mg/kg IV every 12 hours),
foscarnet (Foscavir, 60 mg/kg IV every 8 hours), or cidofovir (Vistide, 5
mg/kg IV every day) for 2 to 3 weeks can be used as alternatives. Colitis
and esophagitis are treated with ganciclovir (Cytovene) or foscarnet
(Foscavir) for at least 3 to 4 weeks or until symptoms resolve. A
combination of ganciclovir (Cytovene) and foscarnet (Foscavir) until
symptoms resolve is required for the treatment of neurologic disease.
Secondary prophylaxis can be discontinued if CD4 is more than 100 to
150 cells/L for 6 months. However, regular ophthalmologic monitoring
should be done to detect relapse early. IRIS occurs in most of the patients
with CMV retinitis following initiation of HAART, resulting in vitreitis
or uveitis. Periocular steroids or short courses of oral steroids often
control the symptoms.
Tuberculosis in HIV-Infected Patients

Tuberculosis is the most common OI in HIV-infected patients from
developing countries. In contrast to other OIs, tuberculosis can occur at
any level of CD4 count. Extrapulmonary and disseminated forms
become more common as the immunosuppression worsens. Meningeal
and miliary dissemination often occurs. In advanced immunosuppression,
typical cavitary and sputum-smear-positive pulmonary disease are seldom
seen. Diagnostic and therapeutic approaches to tuberculosis remain the
same as in a HIV-negative patient, except that once-weekly rifapentine
(Priftin) and if CD4 counts are less than 100 cells/mL, twice-weekly
rifabutin (Mycobutin)1 should not be used. Standard four-drug shortcourse regimens (see chapter on tuberculosis) are equally effective in
HIV-infected patients with drug-susceptible tuberculosis. All patients
should receive directly observed treatment, and thrice-weekly intermittent
regimens can be used. Extensive interactions occur between rifamycins,
PIs, and NNRTIs. If the patient is already on HAART, rifabutin
(Mycobutin) is the preferred rifamycin, and HAART has to be continued
with appropriate changes (Table 10). If the patient is not on HAART, it
is better started after the completion of the intensive phase in those with
CD4 more than 200 cells/mL. In those with CD4 less than 200
cells/mL, it is preferable to initiate HAART early, after approximately 2
weeks of intensive-phase treatment.
1
DM, March 2008
191
TABLE 10. Pharmacokinetic Interactions between Antiretrovirals and Rifamycins

Compatibility with Rifampicin (Rifadin)
Antiretroviral Drug
Antiretroviral Dose
Change
Saquinavir
(Invirase,
Fortovase)
Saquinavir/ritonavir
(Invirase,
Fortovase/Norvir)
Indinavir (Crixivan)
Nelfinavir (Viracept)
Amprenavir
(Agenerase)
Atazanavir
(Reyataz)
Lopinavir/ritonavir
(Kaletra)
Efavirenz (Sustiva)
Nevirapine
(Viramune)
Delavirdine
(Rescriptor)
Rifampicin
(Rifadin)
Dose
Change
Should not be used together
Compatibility with Rifabutin

(Mycobutin)
Antiretroviral
Dose Change
Rifabutin
(Mycobutin)
Dose Change
None
2 150 mg qod*

1 1000 mg tid
1 1000 mg tid
None
2 150 mg qd
2 150 mg qd
2 150 mg qd
None
2 150 mg qod*
(2 400/1 400) mg bid
None
(400/1 400) mg bid
None
None
2 150 mg qod*
1 800 mg qd
None
None
None
None
None
1 450 mg qd
None
Note: Increase or decrease in the doses are indicated with appropriately directed arrows.
Based on Centers for Disease Control and Prevention: Updated guidelines for the use of rifamycins for the
treatment of tuberculosis among HIV-infected patients, 2004.
*Can be administered as 150 mg tiw.
Can be administered as 300 mg tiw.
Can be administered as 600 mg tiw.
Management of the Pregnant HIV-Infected Woman

Apart from the usual indications for initiating HAART, in a pregnant
HIV-infected woman, an additional aim is to prevent perinatal transmission. This is most effectively achieved by suppressing viremia to
undetectable levels with HAART. From this perspective, all pregnant
HIV-infected women should be initiated on HAART, irrespective of the
viral load, CD4 count, and symptoms. Efavirenz (Sustiva), a combination of didanosine (Videx) and stavudine (Zerit), nevirapine (Viramune)
in those with CD4 more than 250 cells/L, and oral liquid formulations
of amprenavir (Agenerase) should be avoided. Although NRTIs and
nevirapine (Viramune) can be administered in the usual adult doses,
nelfinavir (Viracept) has to be given only twice daily (Table 4). Initiation
is better timed at the second trimester, to improve the tolerability and to
avoid early fetal exposure to antiretrovirals. A detailed second-trimester
fetal survey is indicated.
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DM, March 2008
The goal of treatment, follow-up assessment, and indications for

resistance testing all remain the same as in a nonpregnant patient.
HAART has to be continued without interruption through delivery.
Intrapartum, zidovudine (Retrovir) has to be administered IV until the
umbilical cord is clamped and other drugs can be continued by oral route.
The option of elective cesarean delivery should be offered to patients with
viral loads higher than 1000 copies/mL despite HAART. If opted for,
elective cesarean delivery is performed at 38 weeks gestation, avoiding
an amniocentesis to document fetal lung maturity. Following delivery, the
infant should receive zidovudine (Retrovir) for 6 weeks. To avoid
transmission through breast milk, nursing the infant should be avoided
completely, if resources permit. Where the sole indication for initiating
HAART was the prevention of perinatal transmission, HAART may be
discontinued (in a staggered fashion, if nevirapine [Viramune] was
included) after delivery. All infants exposed to antiretrovirals in utero
should be followed up for possible adverse effects, regardless of the HIV
status. Combined together, these interventions, namely HAART, cesarean
delivery, and avoidance of breast-feeding, have brought down the risk of
mother-to-child HIV transmission from approximately 25% to 1-2% in
developed countries. In resource-limited settings and for HIV-infected
women without prior HAART presenting in labor, peripartum prophylaxis with zidovudine (Retrovir), zidovudine with lamivudine (Combivir),
nevirapine (Viramune), or zidovudine with nevirapine are acceptable
alternatives.
Postexposure Prophylaxis of HIV Infection

The importance of adhering to universal precautions in preventing
occupational transmission of HIV cannot be overstated. Administration of
postexposure prophylaxis (PEP) can substantially reduce the risk of HIV
transmission following accidental occupational exposure in the health
care setting. However, PEP is associated with significant morbidity and
potentially serious side effects. HIV testing of the health care personnel
should be done at the time of exposure and at 6 weeks, 12 weeks, and 6
months after exposure. Generally, all grades of percutaneous, mucous
membrane, and nonintact skin exposure to a known HIV-infected source
warrant administration of PEP. In the case of mucosal or nonintact skin
exposure to a small volume (a few drops) of body fluid from a known
HIV-infected source, the decision to initiate PEP should be made on a
case-to-case basis, after discussing with the exposed person the benefits as
well as the risks of PEP.
PEP should be initiated as soon as possible, preferably within hours
DM, March 2008
193
following the exposure. The basic prophylaxis is with a two-drug

regimen, usually a combination of two NRTIs (zidovudine lamivudine
[Combivir] or emtricitabine tenofovir [Truvada]). If the exposure is
more severe, three-drug regimens containing a PI are recommended. PEP
is to be given for 4 weeks. If the source serostatus is unknown,
administration of basic prophylaxis should be considered if the source is
likely to be HIV-infected and the exposure was percutaneous or involved
a large volume of potentially infectious body fluid. The recommendations
for PEP were extended recently to include nonoccupational exposures
also (e.g., those reporting within 72 hours following an unanticipated
sexual or injection drug use exposure to a known HIV-infected source).
Current Diagnosis
Threshold to offer HIV testing to a patient should be low; nonselective
HIV testing in health care settings could be cost effective.
A repeatedly reactive enzyme immunoassay, rapid test, or nucleic
acid-based test for HIV infection needs confirmation with a Western
blot assay.
Estimation of CD4 count and plasma viral load should be performed
to assess the need for antiretroviral therapy and the risk of opportunistic infections.
Current Therapy
History of any AIDS-defining illness, CD4 count 200 cells/L, and
symptomatic HIV disease warrant initiation of highly active antiretroviral therapy (HAART).
HAART should be offered also to patients with CD4 counts 200-350
cells/L, irrespective of viral load and symptoms.
HAART can be deferred if CD4 count is 350 cells/L with plasma
viral load below 100,000 copies/mL.
Once initiated, HAART has to be continued lifelong without interruption.
Adherence is a very important determinant of virologic outcome.
Regular monitoring of viral load should be done to diagnose treatment
failure early.
At least two fully active drugs, based on treatment history and
resistance testing, should be included in the salvage regimen.111
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DM, March 2008
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Management of The Patient With HIV Desease

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Management of The Patient With HIV Desease

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Management of the Patient with HIV

DM, March 2008

The Causative Agent

sion worldwide, especially in developing countries. In the United States,

DM, March 2008

TABLE 1. Acute HIV Syndrome*

*Occurs approximately 3 6 wk following primary infection; symptoms last for 1 to several

Pathogenesis and Natural History of HIV Infection

DM, March 2008

Note: Shading distinguishes risk: 2% no shading; 2%9.9% light gray; 10%19.9%

and GB virus C. CMV co-infection possibly augments the rate of HIV

Changing Face of HIV/AIDS

Whom to Test for HIV Infection

DM, March 2008

correctional facilities, should also be offered HIV testing. HIV infection

Diagnosis of HIV Infection

Management of the HIV-Infected Patient

DM, March 2008

not report any of the known risk factors. A nonjudgmental approach is

lesions of Kaposis sarcoma, and aphthous ulcerations while examining

DM, March 2008

TABLE 3. Initial and Subsequent Laboratory Evaluation of the HIV-Infected Patient

Annually, if sexually activef

May be repeated more frequently if clinically indicated.

resistance, place the patient unduly at risk of disease progression and

TABLE 4. Currently Approved Antiretroviral Drugs

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Ritonavir, if given for boosting, should not be administered simultaneously.

DM, March 2008

TABLE 5. First-Line Antiretroviral Regimens for Treatment-Nave HIV-1-Infected Patients

When to Initiate HAART?

making. Initiation of HAART is warranted in patients with history of any

Monitoring Response to Antiretroviral Therapy

DM, March 2008

Drug Resistance and Resistance Testing

more than 50 copies/mL after 48 weeks of treatment in a drug-nave

DM, March 2008

TABLE 6. Salvage Therapy in Patients with Treatment Failure (Virologic Failure)

2 NRTIs (based on resistance

2 NRTIs (based on resistance

2 NRTIs (based on resistance

to 10% of doses is known to affect virologic outcome adversely. The

ence counseling and assessment of adherence should be done at each

Adverse Drug Reactions and Drug Interactions

DM, March 2008

TABLE 7. Approach to Adverse Drug Reactions in the HIV-Infected Patienta

Fever, diffuse rash,

PIs, ddI, ZDV

DM, March 2008

ddI, d4T, ddC,

ddI, d4T, ddC

metabolized by the hepatic cytochrome P450 (CYP) enzymes. At the

DM, March 2008

peutic drug levels. In a patient on HAART, unnecessary prescriptions are

Management of Opportunistic Conditions

Assess cardiac risk

justified in acutely ill patients. In a patient with a severe OI as the initial

DM, March 2008

inflammatory syndrome (IRIS). However, in patients with OIs for which

Pneumocystis Jiroveci Pneumonia (PCP)

TABLE 8. Primary Chemoprophylaxis for Opportunistic Infections in the HIV-Infected Patient*,

Primary chemoprophylaxis not recommended for cytomegalovirus, Cryptococcus neoformans, Histoplasma

Not prophylaxis in strict sense.