Human immunodeficiency virus

OVERVIEW: What every practitioner needs to know

Are you sure your patient has human immunodeficiency virus? What are the typical findings for this disease?

In pediatrics, human immunodeficiency virus (HIV) infection primarily occurs in two patient populations: infants and children who acquired the virus from their mother during gestation or in the perinatal period, and adolescents who acquired the virus through adult risk behaviors (ie, sex or recreational drug use). Transmission through exposure to blood products has been virtually eliminated through screening of blood donors.

Infants with perinatally acquired HIV are typically asymptomatic at birth, but >90% develop symptoms by 3 years of age if untreated. Adolescents who acquire HIV may experience an acute retroviral syndrome within 2-6 weeks of infection, but symptoms resolve spontaneously within several weeks; many youth enter a period of "clinical latency" with minimal, if any, symptoms for years, while others develop symptoms within 1-2 years.

If untreated, HIV continues to replicate at detectable levels in the blood and other reservoirs in the body, and the level of CD4+ T-lymphocytes, the major target of HIV infection, eventually declines; when the CD4 cell count becomes severely depleted, symptoms of the Acquired Immunodeficiency Syndrome (AIDS) develop. AIDS is a clinical diagnosis defined by the presence of certain opportunistic infections, malignancies, and HIV-associated central nervous system disease (Table I).

Table I

Treatment of HIV with antiretroviral therapy (ART) is effective but most of the drugs have potential toxicity and strict adherence to the medication regimen is demanding.

There are two types of HIV, HIV-1 and HIV-2, which have similar clinical courses, although HIV-2 is generally less aggressive. HIV-2 is predominantly found in West Africa, and is rare elsewhere in the world. This monograph will use "HIV" to refer to HIV-1, the type found in the United States (US), and will primarily cover HIV disease as it presents and is treated in high-resource settings such as in the United States and Europe.

Typical findings for HIV infection

A combination of nonspecific but recurrent or persistent symptoms should prompt consideration of HIV infection, such as:

- oral candidiasis

- generalized lymphadenopathy (axillary adenopathy is especially indicative)

- hepatosplenomegaly

- recurrent otitis media and/or sinusitis

- recurrent diarrhea

- intermittent fever

- poor growth or weight loss

- or developmental delay.

Involvement of the central nervous system is more commonly seen in HIV-infected children than adults, and may be subtle (e.g., developmental delay) to more significant (symmetric motor dysfunction, acquired microcephaly or cognitive decline). With advanced disease, symptoms suggestive of severe immunodeficiency ensue, such as wasting, encephalopathy, opportunistic infections and/or unusual malignancies.

Natural history

Before highly active therapy was available, children presented with one of three patterns of HIV disease. Approximately 15-25% had rapidly progressive disease with early onset of failure to thrive, opportunistic infections and encephalopathy in the first year of life and a median untreated life expectancy of less than 1-2 years; this pattern still predominates in resource-limited countries (such as sub-Saharan Africa and southeast Asia) where access to therapy is limited.

The majority (60-80%) of children in high-resource countries had slowly progressive disease with less acute symptoms and a median survival of 6 years. The most common symptom complexes for these children included recurrent bacterial infections (bacteremia/sepsis or pneumonia with S. pneumoniae, Salmonellasp., H. influenzaeor other encapsulated organisms, or otitis media with chronic drainage, or sinusitis), generalized lymphadenopathy, or lymphocytic interstitial pneumonitis (LIP, see below).

The third group (<5%) were long-term non-progressors, who had minimal, if any, symptomatology, a low virus burden and good immunologic function in the absence of treatment; their life expectancy was at least 8 years, and usually much longer. Initiation of antiretroviral therapy early in life has made rapidly progressive disease uncommon.

While the course of disease is similar to that in adults, adolescents frequently come to medical attention later in the course of illness with more advanced immunodeficiency. 30 to 60% may experience an acute retroviral syndrome with spontaneous resolution of symptoms; thereafter there is an asymptomatic period which may extend from 6 months to years, followed by moderate symptoms of immunocompromise, such as recurrent or persistent oral or vaginal candidiasis, recurrent or multidermatomal herpes zoster, persistent low grade fever or diarrhea. AIDS-defining conditions (See Table I) occur when the CD4 count has significantly declined, with the greatest risk at <75 CD4 cells/mm3.

Staging of HIV disease

An HIV classification system is used by the Centers for Disease Control and Prevention (CDC) to stage the disease for surveillance and research purposes (Table II).

Table II

For adolescents and adults, the system primarily uses the CD4+ T lymphocyte count (measured as cells/mm3blood) and relies less on clinical symptoms: Stage 1 is a CD4 count or percentage of >500 cells/mm3or >29%, stage 2, 200-499 cells/mm3or 14-28%, and stage 3, <200 cells/mm3or <14%. Stage 3 disease fits the case definition for AIDS, which also can be fulfilled by diagnosis of an AIDS-defining condition.

The classification for children <13 years of age (Table III) incorporates clinical findings into all of the stages, with categories N, A and B describing no, mild or moderate signs and symptoms, respectively, and C including AIDS-defining diagnoses. The immunologic categories rely more heavily on CD4 percentage than absolute number in children, as absolute CD4 numbers are very high at birth and slowly decline to adult levels ~6 years of age, while the CD4 percentage remains stable throughout that period.

Table III

Immunologic categories 1 (no suppression), 2 (moderate suppression) and 3 (severe suppression) use cut-offs of >25%, 15-25% and <15% of CD4+ T-lymphocytes. Therefore, a child's CDC stage is a combination of clinical and immunologic categories, for example, A2 describes a child with mild symptoms and moderate CD4 suppression.

To monitor overall disease status and response to therapy, clinicians monitor the plasma viral load, or HIV-1 RNA level, measured as number of viral copies/ml blood, and the CD4 count to indicate the immunologic status and need for prophylaxis to prevent AIDS-defining infections. The goal of therapy is to render the viral load undetectable (<50 copies/ml) and restore the CD4 count to >25% (or >500 cells/mm3for adolescents), as well as to reduce morbidity/mortality and improve the patient's quality of life.

What other disease/condition shares some of these symptoms?

Other immunodeficiency diseases may present with similar symptoms, for example, severe combined immune deficiency (SCID), CD40 or CD40 ligand deficiency (formerly called Hyper-IgM syndrome), X-linked aggamaglobulinemia, common variable immunodeficiency, and chronic mucocutaneous candidiasis. Severe malnutrition, typically seen only in resource limited countries, may have a similar presentation with cachexia, oral thrush and overwhelming infections.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Diagnostic Testing for HIV Infection

Diagnostic testing should be performed on whole blood, serum or plasma and varies by age. Note that any positive test must be confirmed with a repeat age-appropriate assay from a separate blood sample drawn at a different time before a definitive diagnosis can be made.

Children >18 months, adolescents and adults: HIV antibody testing with confirmatory Western blot OR two positive HIV rapid tests made by different manufacturers should be performed. A confirmed positive HIV antibody test with Western blot is diagnostic.

Children <18 months: A specific virologic test is necessary; HIV antibody testing in this age group may be misleading due to placental transfer of maternal HIV antibody, which can persist in the infant up to 18 months of age, even if the infant is not HIV-infected.

Diagnosis of perinatally acquired HIV in an infant: a specific virologic test should be performed at 14-21 days, 1-2 months, and 4-6 months of age; if all of these tests are negative, the infant does not have HIV infection. If any one of these tests is positive, a repeat virologic test on a second blood sample should be obtained as soon as the first result is available to confirm the diagnosis. The sensitivity of the HIV DNA PCR in perinatally acquired HIV is 96-98% by one month of age and almost 100% at 3 months of age for HIV subtype B (the primary subtype in the USA). DNA PCR may not be sensitive for refugees from Africa or Asia where non-subtype B HIV predominates.

Clinical clues which warrant evaluation for HIV

Children who present with unusual or recurrent infections indicative of immune dysfunction should be evaluated for HIV infection; for example, severe or prolonged varicella, recurrent or disseminated varicella zoster, frequent or extensive episodes of herpes simplex labialis, oral thrush over 1 year of age, prolonged diarrhea contributing to weight loss, recurrent fevers, or any opportunistic infection. In addition, any combination of poor growth, chronic lymphadenopathy, chronic or recurrent infections or developmental delay should prompt testing for HIV infection, in particular if the mother's HIV status is unknown.

Adolescents who present with symptoms of acute retroviral syndrome should have an HIV antibody test, and if negative, a specific virologic test should be performed, as HIV antibody may not be detectable for 6-12 weeks after infection. Adolescents who present for testing immediately after an unprotected sexual encounter should be tested for HIV antibody to establish prior infection, and if negative, retested 3 months later. Post-exposure prophylaxis therapy should be considered following sexual assault or unprotected sex with a known HIV-infected person.

If you are able to confirm the patient has HIV, what treatment should be initiated?

Because HIV disease may progress rapidly in infants <12 months of age, antiretroviral therapy (ART) should be initiated in all infants in this age group, optimally before 12 weeks of age. Decisions about initiating ART in older children or adolescents depends on the patient's symptoms, CD4+ T-lymphocyte count/percentage +/- the HIV RNA level in the blood (measured in copies/ml) (Table IV & Table V).

Table IV

Table V

The patient and/or caregiver should be thoroughly educated about the importance of ARV adherence prior to initiation of therapy, as poor or inconsistent adherence will lead to selection of HIV drug resistance mutations.

There are >20 FDA-approved antiretroviral drugs (ARVs) for treatment of HIV disease ( Table VI). A combination of three to four ARVs (combination antiretroviral therapy or cART) is recommended for initial and long term therapy; this typically consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Most PI's require pharmacologic "boosting" with ritonavir, a PI which lengthens the half-life of other PI's by decreasing clearance through inhibition of the cytochrome P450 3A4 enzyme.

Table VI

Considerations for selecting specific agents include potency, incidence and type of specific short- and long-term toxicities, dosing frequency (once versus twice daily), pill or liquid burden, potential for drug interactions and tolerability issues. ARV drug-resistance testing (genotype or phenotype tests, available through reference labs) should be performed prior to initiation of therapy.

Experts in treatment of Pediatric or Adolescent HIV should be consulted before selecting an ARV regimen. Guidelines for selecting an appropriate regimen developed by the Department of Health and Human Services' Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children are available at

What are the adverse effects associated with treatment?

Nucleoside reverse transcription inhibitors (NRTIs): this class of ARVs is generally well tolerated but may have toxicity with long term use; i.e. the thymidine analogues (stavudine>didanosine>zidovudine) have been associated with mitochondrial toxicity such as lactic acidosis, and lipoatrophy.

Zidovudine is associated with macrocytic anemia or neutropenia in up to one third of individuals. Abacavir is associated with a rare (<5%), but life-threatening, hypersensitivity reaction; the HLA B*5701 gene assay can be used to identify individuals at higher risk for this reaction, but this test is most predictive for Caucasians and less so for other racial groups.

Tenofovir has been associated with reduced bone mineralization in adults and is not approved for use in children <12 years of age; if used in adolescents with less than Tanner 5 pubertal development, bone mineralization surveillance should be considered. Furthermore, tenofovir has been associated with a modest decline in glomerular clearance rate and subclinical tubular dysfunction in adults, so renal function should be monitored with this drug.

Non-nucleoside reverse transcription inhibitors (NNRTI's): this class of ARVs may cause a diffuse maculo-papular rash in up to 30% of patients. It often resolves despite ongoing drug exposure, however, any mucous membrane involvement or disturbance of liver or renal function is reason to discontinue the drug. Nevirapine has been associated with reversible liver toxicity but rare cases of liver failure and death have been reported. Efavirenz has been associated with sleep disturbance, dizziness and rarely, psychiatric symptoms, which resolve when the drug is discontinued; in addition, it has been found to be teratogenic in nonhuman primates, therefore effective contraception methods should be required when used in adolescent females. Hypersensitivity reactions including rash are infrequently seen with etravirine.

Protease Inhibitors (PIs): This class of drugs, in general, has the lowest tolerability, and has been most associated with gastrointestinal upset (diarrhea and/or nausea and vomiting); other toxicities may include liver enzyme elevation, serum lipid elevation (especially triglycerides) and central fat accumulation (lipodystrophy, see Complications, below.)

Other newer classes of antiretroviral drugs, such as integrase inhibitors and entry inhibitors, are still undergoing evaluation in children.

Many ARVs, especially the PIs and NNRTIs, have multiple drug-drug interactions with ARVs and other classes of drugs. A pharmacist experienced in the use of ARVs should be consulted to investigate possible interactions before prescribing these drugs.

What are the possible outcomes of this disease?

Mortality from HIV/AIDS has been reduced by >90% by the introduction of cART, and HIV/AIDS, with appropriate treatment, can now be considered as a chronic disease. However, antiretroviral therapy is life-long and requires pristine adherence to antiretroviral therapy for viral control and immunologic reconstitution; the day-in-day-out requirement of cART therapy remains a substantial challenge for many caregivers of young children, who may resist taking unpalatable liquid formulations of ARVs, as well as for older HIV-infected children and adolescents. Nonadherence increases the likelihood of selection of ARV resistance mutations which may lead to loss of virologic suppression and ultimately, disease progression and death.

Important clinical presentations to recognize

The most common life-threatening presentation of HIV is Pneumocystis jiroveci (formerly P. carinii) pneumonia (PCP). The hallmark features include fever, tachypnea and hypoxemia with rapid progression to respiratory failure; chest x-ray shows diffuse interstitial or alveolar infiltrates. Diagnosis is made by demonstrating the organism in broncho-alveolar lavage. PCP can be prevented by trimethoprim/sulfamethoxazole (TMP/SMX), given when the CD4 count falls below 15% (young children) or <200 cells/mm3 (> 6 years of age). PCP primarily occurs in infants or adolescents with previously undiagnosed HIV or HIV-infected patients not adherent to TMP/SMX prophylaxis.

A chronic lower respiratory tract process unique to children with HIV is lymphocytic interstitial pneumonitis (LIP); evidence suggests this is the result of a poorly controlled lymphoproliferative response to a primary Epstein Barr virus infection. LIP presents with insidious onset of tachypnea and hypoxemia, with a typical reticulonodular infiltrate +/- hilar lymphadenopathy on chest x-ray; these radiographic findings may be indistinguishable from PCP, except that they significantly predate the onset of symptoms. Once responsible for ~30% of AIDS diagnoses in children, LIP has become rare in the era of cART.

Painless parotid enlargement (unilateral or bilateral) is another finding more common in children than adults and is often seen in children with LIP.

Complications of HIV disease and its treatment

Lipodystrophy, or abnormal body fat distribution, occurs in 20-60% of individuals taking ARVs. This presents with either lipoatrophy of the face, extremities, and/or buttocks, or central fat accumulation in the viscera and trunk, breasts or cervicodorsal fat pad (buffalo hump), or both. The pathophysiology of this process is not well-defined and is likely due to a combination of mitochondrial toxicity, genetic predisposition, and virus- and drug-mediated effects on adipose tissue.

Insulin levels have been found to be up to 40% higher in HIV-infected children than HIV-negative controls, and up to 15% of patients have impaired glucose tolerance; the latter may correlate with longer duration of ART and higher use of PIs. These youth will need to be followed for possible development of diabetes.

Cardiovascular disease (CVD) occurs at a higher rate in HIV-infected adults than in the general population. Increased carotid-intima-media thickness has been found in perinatally infected youth compared to healthy age-matched controls. When compared with controls, a cohort of 240 HIV-infected children aged 7-24 years was found to have more dyslipidemia (significantly lower high-density lipoprotein cholesterol (HDL) levels and higher mean total low-density lipoprotein cholesterol (LDL) in those taking protease inhibitors). The degree to which children and adolescents with HIV will suffer from accelerated CVD is currently under surveillance.

Adults with HIV have a higher risk of bone fracture than healthy controls. The mechanism for lower bone mineral density (BMD) in HIV disease is not fully elucidated, but is likely to have multiple etiologies, some of which include host factors, disease status, chronic inflammation, low calcium intake and relative vitamin D deficiency, and effects of multiple different antiretroviral drugs. Longitudinal studies have demonstrated a significant decrease in BMD within the first 6 months of initiation of ART which then stabilizes, suggesting a possible role of immune reconstitution in bone loss.

Chronic kidney disease, or HIV-associated nephropathy, is most common among African-American HIV-infected individuals, and presents with proteinuria, +/- elevated serum creatinine, edema or hypertension. The largest series of HIV+ children followed prospectively for renal toxicity (n= 2102) reported a 22% incidence of at least one persistent kidney laboratory abnormality, with an elevated serum creatinine in 15% and proteinuria in 8%.

In adults, HIV is associated with a higher incidence of neoplasms than in the general population, but the association is not as strong in pediatric HIV disease. The incidence of AIDS-defining malignancies has decreased since the introduction of highly active ART. However, the incidence of non-AIDS defining malignancies is increasing and contributes to mortality despite cART; this increase may be related to prolonged survival, co-infections (HPV, hepatitis B and C, EBV) and lifestyle choices (smoking, sun exposure, sexual habits, etc). As adults, children and adolescents with HIV infection will need ongoing surveillance for neoplasms, despite adequate immune reconstitution with ART.

What causes this disease and how frequent is it?

Infants acquire HIV perinatally from an HIV-infected mother, either during gestation (in utero), at the time of delivery (peripartum) or postpartum during breastfeeding. Treatment of HIV+ mothers and their infants with ARVs can successfully prevent mother to child transmission (see Prevention, below) and it is now estimated that <100 HIV-infected infants are born in the US each year, despite more than an estimated 9000 deliveries to HIV+ mothers. However, in resource-poor countries, where 99% of the >2 million HIV infected children in the world reside, limited availability of ARVs and coordinated pre- and perinatal care has remained a challenge, fueling the source of ongoing pediatric HIV infection in these regions.

The adolescent population acquires HIV through high-risk sexual activity (i.e. sex with a partner known to have or be at high risk for HIV infection or males who have sex with males [MSM]) and less frequently, through injection of infected blood through shared needles during IV drug use. In 2006, 15% of new infections in the US occurred in individuals between the ages of 13-24 years; within this sector, African American MSM had the highest incidence, with a doubling in the number of cases between 2001 and 2006.

One third of cases reported to the CDC among youth 13-19 years of age in 2008 were female, with 90% acquiring HIV through heterosexual sex, often with older partners. Injection drug use represented 9.5% of new cases in girls and 2-5% in boys, however, other recreational drugs and alcohol are associated with social disinhibition and increased risk behaviors that predispose to infection. The CDC has estimated that the majority of HIV+ adolescents are unaware of their diagnosis.

In the United States, HIV is over-represented in minority racial/ethnic populations. For example, in 2008, black/African Americans comprised only 17% of the US population of adolescents 13-19 years of age but 75% of HIV infected youth. Perinatally infected children display similar racial disparities.

With the decreasing rate of new infections among infants born to mothers with HIV infection and the rise in adolescent infections, the proportion of HIV+ patients in Pediatrics is shifting from infants/children to adolescents with behaviorally acquired disease.

How do these pathogens/genes/exposures cause this disease?

After a single "founder" virus or HIV infected cell gains access to the body, most frequently through a mucosal surface and less often, directly into the circulation, it intensively replicates and disseminates to lymphoid tissues. This results in a peak plasma viral load of up to 10 million HIV RNA copies/ml and significant CD4+ T-cell depletion. During this time chronic persistent viral reservoirs are established in lymphoid tissues and long-lived resting CD4+ T cells, which contribute to an indefinite ongoing source of newly infected cells.

Perinatally infected infants typically maintain viral loads between 200,000 to 1 million copies/ml for up to 2 years. In contrast, most adolescents and adults have a spontaneous decline in viral load to a lower set point within several weeks as the host immune response, albeit inadequate for virus control or eradication, is generated. A chronic, usually asymptomatic phase of 1->10 years of sustained viral replication and immune activation ensues, which, in the absence of therapy, eventually leads to CD4+ T cell depletion and advanced immune deficiency.

Are additional laboratory studies available; even some that are not widely available?

Hypergammaglobulinemia is a consistent laboratory finding among HIV-infected children, due to polyclonal activation of B cells with HIV infection. Ironically, specific antibody formation is typically impaired.

How can HIV be prevented?

It is now standard of care to test all women for HIV infection during pregnancy. Positive women should be treated with cART early in gestation and intravenous zidovudine during labor and delivery to prevent transmission; infants are then treated with oral zidovudine for the first 6 weeks of life. This regimen has reduced transmission from a rate of ~25% in untreated mother/infant pairs to <2%. Women in labor whose HIV status is unknown should have rapid antibody testing performed so that IV zidovudine therapy can be instituted in the mother and the infant can be appropriately prophylaxed. Women in the US are also advised not to breastfeed, to eliminate this route of exposure.

Prevention in adolescents should focus on safer sexual practices and avoidance of recreational drug use. The CDC has estimated that >50% of HIV+ adolescents are unaware of their diagnosis, many of whom engage in unprotected sex. Condoms, when used consistently and correctly, are highly effective in preventing transmission, with efficacy estimated to be >90%.

Receptive anal intercourse has the highest risk for transmission. Studies in sub-Saharan Africa have demonstrated that male circumcision reduces their risk of acquiring HIV from heterosexual intercourse by over 60%. A double-blind, randomized controlled trial of vaginal 1% tenofovir gel before intercourse showed a 39% overall reduction in incident cases of HIV in women in South Africa.

Pre-exposure prophylaxis (PreP) using a daily dose of a single combination pill of tenofovir and emtricitabine has been associated with a reduction in transmission of at least 44% in adult MSM and 63% in heterosexual partners. Intravenous drug use involving shared needles has the highest risk for HIV transmission but use of other recreational drugs is more frequent and may reduce inhibition and promote unprotected sex.

In 2006, the CDC recommended that "opt-out", voluntary HIV antibody testing should become a part of routine clinical care for all patients aged 13-64 years, that is, informing individuals that HIV testing will be performed unless expressly declined. This initiative aims to promote early diagnosis and treatment. In addition, because it is estimated that sexual transmission is 3.5 times higher among those who are unaware of their diagnosis, routine testing should contribute to adoption of better preventive practices for HIV+ individuals.

What is the evidence?

"Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection". August 11, 2011. pp. 1-268.

(A comprehensive resource of data and recommendations on treatment and management of HIV/AIDS in children, compiled by a panel of HIV/AIDS experts from the United States. This is reviewed and updated on a yearly basis.)

"Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents". March 27, 2012.

(A comprehensive resource of data and recommendations on treatment and management of HIV/AIDS in adults and adolescents, compiled by a panel of HIV/AIDS experts from the US. This is reviewed and updated on a yearly basis.)

(A review of the pathogenesis and immune response of HIV-1 infection.)

(This study randomized infants to immediate versus deferred therapy and found that initiation of ART before 12 weeks of age reduced mortality by 76% and HIV progression by 75%; this has provided the most definitive evidence of the benefit of early diagnosis and initiation of ART in infants.)

(This prospective, multi-center cohort study evaluated the long-term outcomes of >3500 HIV-1 infected US children and found declining mortality in the cART era, but the death rate remains approximately 30 times higher than the general population of children.)

(This article reviews the ongoing challenges to perinatally infected children growing up with HIV/AIDS, as well as the complications of the disease and its treatment.)

(A cross-sectional multicenter study on metabolic abnormalities and lipodystrophy in 240 HIV-infected children/youth compared with HIV-negative controls.)

(A prospective observational trial of renal dysfunction in 2102 children/youth treated for HIV infection.)

Ongoing controversies regarding diagnosis, treatment and management

An ongoing controversy is when to start ART in adolescents and adults. Using the CD4 count as the measure of immunodeficiency, the threshold for initiating ART has vacillated between <350 to <500 CD4 cells/ul. Some studies suggest that initiation of treatment at a higher CD4 count is associated with improved long-term preservation of immune function; recent treatment guidelines recommend (with moderate strength evidence) that ART should be considered for all HIV-infected individuals.

Reasons to delay initiation of ART include postponement of drug-associated toxicities and medication adherence fatigue as well as the cost of the drugs. A second dilemma is what drug regimen is "best" for initial therapy, i.e. a NNRTI-based versus a PI-based versus combination. The two types of regimens appear to be equally efficacious in adults, but have differing toxicities, tolerability and thresholds for development of drug resistance mutations related to adherence requirements.

Development of a vaccine has been a high research priority since the discovery of the virus, but due to the virus' myriad quasispecies, its rapid mutation rate and the need for it to generate a wide-spectrum immune response (i.e. both neutralizing antibodies and cell-mediated immunity), a protective vaccine has not been developed to date.

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