“Adolescence and young adulthood is a unique period characterized by developmental and psychosocial change,” said Dr. Allison Agwu, assistant professor of infectious diseases at Johns Hopkins University and lead author of the study.

“There must be careful consideration about what kinds of clinical sites may be best to provide care for this population,” she added.

The authors of the study speculated that lower patient-to-provider ratios, availability of youth-friendly programs to support treatment adherence, and an increased emphasis on social services and case management might underlie the lower discontinuation rates in pediatric clinics.

The authors emphasized that the findings could help clinicians design treatment strategies that are less likely to be discontinued. Dr. Agwu also suggested that it may be useful to incorporate new technology (such as text messages, emails, and social networking sites), flexible clinic hours, and peer support systems into the overall treatment approach to increase HAART initiation and adherence.

Previous studies have suggested that adolescents may represent a high-risk population for HIV infection, with individuals between 13 and 24 years of age accounting for nearly half of all new HIV infections in the United States.

Adolescents who acquired HIV through sexual exposure or intravenous drug use are called behaviorally-infected youth. They often follow very different clinical trajectories from those who acquired HIV at birth or by blood transfusion.

Previous research has found that significantly fewer behaviorally-infected youth start highly active antiretroviral therapy (HAART) as compared to adult patients. In addition, several studies have noted that teens who start HAART show lower adherence to treatment compared to adults on a similar regimen.

According to the study authors, several factors such as poor clinical attendance, intolerance of side effects, limited parental involvement, and depression can hinder successful HIV treatment among youth.

Since behaviorally-infected youth can be between 12 and 24 years of age, they can be treated at either pediatric or adult clinics. Many pediatric HIV clinics see patients through age 24, while adult clinics may see patients as young as 16 years old.

The study authors hypothesized that treatment at pediatric versus adult clinics may have different effects on HAART initiation and continuation by adolescents.

In this study, researchers retrospectively analyzed data collected between 2002 and 2008 from 14 different HIV clinics across the country. Three of the 14 were pediatric clinics.

A total of 287 behaviorally-infected youth were included in the study. About 68 percent of participants were African-American, and 17 percent were Hispanic. Fifty eight percent were men who have sex with men. Nearly 78 percent of participants attended adult clinics, while the rest attended pediatric clinics.

All participants were between 12 and 24 years of age and had not undergone HAART previously. All participants were eligible for HAART, as they had two successive CD4 (white blood cell) counts below 350 cells per microliter.

The researchers compared the effect of various parameters, including treatment at pediatric versus adult clinics, on the time between becoming eligible for HAART and initiating HAART. They also examined the effect of a number of factors such as sex, race, and type of antiretroviral drugs used on adherence to the HAART regimen. Discontinuation was defined as being off of HAART for at least 60 days.

Results from the study showed that 69 percent of participants received HAART during the study period. There was no difference in rate of HAART use between adolescents treated at pediatric and adult clinics (64 percent versus 70 percent) or time between HAART eligibility and HAART initiation.

Participants with CD4 counts below 200 cells per microliter and participants who visited their HIV clinicians four or more times per year (as recommended by U.S. Department of Health and Human Services treatment guidelines) were more likely to initiate HAART.

Among the participants who started HAART, 29 percent subsequently discontinued it. However, only 15 percent of adolescents at pediatric clinics discontinued HAART, compared to 33 percent at adult clinics. Patients at pediatric clinics also stayed on HAART longer than patients at adult clinics (a median of 1,059 days versus 467 days).

The likelihood of discontinuing HAART was not significantly different between protease inhibitor-based and non-nucleoside reverse transcriptase inhibitor-based regimens. There was also no association between sex or race and likelihood of treatment initiation or continuation.

For more information, please refer to the study in the Journal of Adolescent Health (abstract).

Most (84 percent) of the children in the study who did not survive were born before 1994, at least three years before highly active antiretroviral therapy (HAART) became widely available.

“As antiretroviral utilization milestones were achieved throughout the course of this study, in going from single-agent to dual-agent and then to triple-agent therapy (Highly Active Antiretroviral Therapy – HAART), there have been dramatic parallel improvements in mortality rates among the cohort resulting in prolonged overall survival,” said Dr. Bill Kapogiannis, program director of the Adolescent Medicine Trials Network for HIV/AIDS Interventions and lead author of the study.

However, the study authors noted that despite the large reductions in death rates, the average annual death rate of HIV-positive children during the HAART era remained 50-fold higher than the death rate of HIV-negative children of the same age during the same period in the United States.

They hypothesized that this may be due to increased susceptibility to death from other causes besides HIV, such as non-AIDS-defining infections.

“During this period, as deaths associated with opportunistic infections declined, the numbers of deaths not associated with these infections remain and thus, become more prominent,” said Dr. Kapogiannis.

HAART is defined as therapy involving at least three antiretroviral drugs, usually two nucleoside reverse transcriptase inhibitors combined with either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase inhibitor.

Since the introduction of HAART during the mid- to late-1990s, the frequency of deaths in adults and children with HIV has decreased considerably.

According to the study authors, while trends in survival and death among HIV-positive children have been examined in previous clinical trials, these trials have enrolled patients anytime from birth throughout childhood. As a result, deaths early on when children are particularly susceptible to infections might have been overlooked.

In this study, investigators compared death rates from birth in HIV-positive children born between 1986 and 2004. In particular, the researchers examined three time periods: the no antiretroviral therapy/monotherapy period from 1986 through 1990, the monotherapy/dual therapy period from 1991 through 1996, and the HAART period from 1997 through 2004.

The multicenter, retrospective study included HIV-positive pregnant women and their newborns in four cities in the U.S.: New York, Atlanta, Baltimore, and Newark, NJ. A total of 364 HIV-positive children were included in the study.

Results showed that the death rates of children in the first period and the second period were six and two times higher, respectively, than the death rate of children in the HAART era. However, the death rate in the HAART era remained 50 times higher than that of HIV-negative children of the same age.

The six-year survival rates for children born in the three eras were 57 percent, 76 percent, and 91 percent, respectively.

In addition, the 10-year survival rate for children who received HAART at any age was 94 percent, compared to 45 percent for children who did not receive HAART.

Eighty-one percent of deaths in the study occurred in children aged 3 years or less, and 61 percent of deaths occurred in children aged 2 years or less.

Results also showed that the percentage of deaths due to opportunistic infections declined over time, from 32 percent in 1986 to 1990, to 17 percent in 1991 to 1996, to 9 percent in 1997 to 2004.

The three most common causes of death in the study were end-stage AIDS (24 percent), opportunistic infections (19 percent), and pneumonia (15 percent).

Children who died were more likely to be born in the late 1980s or early 1990s, have a birth weight of less than 5.5 pounds (2.5 kg), be born prematurely (less than 37 weeks), or have low weight or height for their age at three months old. Children with thymic dysfunction, children who were infected with HIV before birth, and children who had not received zidovudine (Retrovir) during and before birth to prevent HIV infection were also at greater risk of death.

HIV transmission from mother-to-child before birth was associated with greater risk of death compared with HIV transmission during labor and delivery; however, the effect was only significant until two years of age.

For more information, please see the study in the Journal of Clinical Infectious Diseases.

“Our study showed a good capacity for immunological recovery in pediatric patients infected by HIV, with CD4 response maintenance in subsequent years,” said Dr. Lílian Diniz, lead investigator of the study, in correspondence with The AIDS Beacon.

“Children in treatment without viral response are still able to recover their CD4 [percentages] to good levels,” she added. “Immunological and virological response could be observed in all age groups and was not associated with lower ages.”

The authors of the study suggested that their results may provide insight into the appropriate timing of the initiation of antiretroviral therapy in HIV-positive children.

“The beginning of therapy before severe [immune] suppression occurs seems to be more effective for recovery or maintenance of normal CD4 levels,” said Dr. Diniz.

The advancement of antiretroviral therapy has improved the quality of life for many individuals with HIV and made HIV a manageable disease, including in children. However, children taking antiretrovirals can face unique challenges, such as adherence problems during childhood and adolescence and side effects that arise from taking antiretrovirals for so long and from such a young age.

As a result, researchers are interested in the long-term efficacy and safety of antiretrovirals in children. The efficacy of highly active antiretroviral therapy (HAART) in children with HIV is mainly defined by viral load (amount of HIV in the blood) and CD4 (white blood cell) counts or percentages.

The researchers in this study analyzed the long-term effect of HAART on the immune response and viral load of 196 HIV-positive children in Brazil from 1998 to 2006. The children ranged in age from 0 to 12 years, with an average age of 3.4 years. Baseline CD4 counts and viral loads were obtained at the beginning of the study.

The children were followed over their first three years of treatment. CD4 counts and viral loads were measured every 24 weeks until week 144.

Immune response was defined as CD4 percentages of at least 25 percent (normal CD4 percentages in children are usually above 25 percent), and undetectable viral loads were defined as less than 50 copies per milliliter of blood. Viral failure was defined as viral loads of 50 copies per milliliter of blood or more.

Most of the children, 68 percent, initiated treatment with a protease inhibitor-based regimen and the rest with a non-nucleoside reverse transcriptase inhibitor-based regimen. During the study period, 34 children switched their HAART regimens, seven children discontinued HAART, and six children died.

Results showed that the children’s average CD4 cell percentage was above 25 percent after 24 weeks of HAART. Children with baseline CD4 percentages between 15 and 24 percent had a four times higher chance of achieving a CD4 percentage of 25 percent or higher by week 24 compared to children with baseline CD4 percentages less than 15 percent.

The results also showed that female children were five times more likely to develop an immune response at week 24 compared to male children.

“Females’ better CD4 response was observed and is possibly related to better conditions at presentation as well as stronger immunological responses during the initial phases of treatment,” noted Dr. Diniz.

The researchers measured viral loads for 122 of the children at week 24. Of these, 45 percent had undetectable viral loads at weeks 24 and most (87 percent) maintained viral suppression at week 144.

However, 54 percent of children had detectable viral loads after 24 weeks of HAART. In addition, 89 percent of these children did not achieve viral suppression later in the study.

The researchers noted that children with higher baseline viral loads were less likely to have undetectable viral loads after 24 weeks of HAART.

Viral failure occurred in seven patients after initial viral response.

CD4 cell improvement was lower and delayed in children with poor viral suppression. However, on average, these children still managed to achieve CD4 percentages of at least 25 percent after 48 weeks of HAART.

There were no significant differences in overall height and weight between children with both immune response and viral response versus children with immune response but viral failure. There was also no link between the children’s age and their chance of reaching viral suppression or having an immune response.

For more information, please see the study in HIV & AIDS Review (abstract).

Highly active antiretroviral therapy has improved over the past 15 years and is now more effective, less toxic, and easier to take than earlier treatment regimens. However, there is still room for improvement, according to Dr. Patrick Yeni, the head of infectious diseases at the Hospital Bichat Claude Bernard and a professor of medicine at the University of Paris, during a presentation at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

“HAART in 2011 is certainly better tolerated than it was in 1996. However, it remains associated with significant toxicity, underlining the fact that we are still in need of better, new drugs,” said Dr. Yeni.

Highly active antiretroviral therapy (HAART) is the combination of at least three antiretroviral drugs, usually two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor, integrase inhibitor, or non-nucleoside reverse transcriptase inhibitor (NNRTI).

Since its development in 1996, the safety and efficacy of HAART have improved due to the availability of more active drugs with fewer side effects and simpler dosing schedules.

However, HAART is still associated with significant side effects and does not eliminate much of the immune dysfunction and inflammation that still occur in people with HIV. These issues can lead to heart disease, bone disease, and a number of other problems over time.

Furthermore, since HAART does not cure HIV, “Antiretroviral therapy is a lifelong therapy,” said Dr. Yeni.

As a result, said Dr. Yeni, future research is needed to investigate both new antiretroviral and non-antiretroviral drugs, as well as therapies that could potentially cure HIV.

New Antiretroviral Drugs And Drug Combinations

Dr. Yeni described several new and next generation antiretroviral drugs currently in clinical trials.

Most of these are from existing drug classes: new NRTIs, protease inhibitors, NNRTIs, and integrase inhibitors. There are also two new drugs from the same class as Selzentry (maraviroc), CCR5 inhibitors, that are currently in Phase 2 trials.

Dr. Yeni noted that some of these new drugs offer advantages over currently approved antiretrovirals. For example, festinavir is a modified form of stavudine (Zerit) that is 100 times less toxic in laboratory tests and therefore might have fewer side effects. It is being developed by Bristol-Myers Squibb and is in Phase 2 clinical trials. CMX-157 and GS-7340 are modified versions of Viread (tenofovir) that are more active against HIV in the laboratory. They are both still in Phase 1 trials.

In addition, two of the drugs that are in Phase 2 clinical trials are not in existing drug classes. BMS-663068, developed by Bristol-Myers Squibb, binds to a protein called gp120 on the surface of HIV. The virus uses this protein to bind to and infect immune cells. Ibalizumab, from TaiMed Biologics, binds to a protein on the surface of CD4 (white blood) cells. Both drugs prevent HIV from attaching to and invading immune cells.

Dr. Yeni also discussed possible new strategies for implementing HAART. In particular, he suggested that in the future there may be changes in the drug combinations used for initial therapy.

He discussed several likely possibilities in this regard, such as the inclusion of CCR5 inhibitors like Selzentry in initial treatment regimens; the replacement of the two-NRTI treatment backbone with alternate antiretrovirals, such as one NRTI plus a protease inhibitor; and even a fully alternative drug regimen, without any NRTIs or protease inhibitors, as new classes of antiretroviral drugs are developed and physicians try to minimize side effects.

Dr. Yeni also suggested that in the future everyone may be treated as soon as they test positive for HIV. Only people whose immune systems can control the virus naturally without antiretrovirals would not start treatment.

“It might well be in the future that the question about initiation of antiretroviral therapy could [involve] the identification of patients who should not receive antiretroviral therapy,” said Dr. Yeni. He suggested this would be based on immune and virological parameters, such as CD4 counts and viral loads (amount of HIV in the blood), but also eventually on a person’s genetics.

Non-Antiretroviral Drugs And Therapies

Dr. Yeni also briefly discussed complementary, non-antiretroviral therapies that could be used to treat immune dysfunction and inflammation in people with HIV.

“These abnormalities have been implicated in the premature onset of several diseases, including cardiovascular [disease], cancer, and osteoporosis,” said Dr. Yeni.

He highlighted several strategies to decrease inflammation, including the use of anti-inflammatory drugs such as aspirin and statins (drugs that decrease cholesterol levels in the body).

Researchers are also investigating the use of a protein called IL-7 to increase immune function in people with HIV. IL-7 is a protein that helps immune cells develop and survive.

“There are probably many other approaches currently being investigated,” said Dr. Yeni. He noted that additional strategies to address inflammation would be discussed by Dr. Tim Schacker from the University of Minnesota in a different presentation during the symposium.

For more information, please see the abstract or the webcast on the CROI 2011 website.

La terapia antirretroviral altamente activa (HAART, por sus siglas en inglés) ha mejorado en los últimos 15 años y hoy en día es más eficaz, menos tóxica y más fácil de tomar que los regímenes de tratamiento anteriores. Sin embargo, todavía hay margen de mejora, según el Dr. Patrick Yeni, jefe del departamento de enfermedades infecciosas del Hospital Bichat Claude Bernard y profesor de medicina en la Universidad de París, durante una presentación en la “18ª Conferencia Sobre Retrovirus e Infecciones Oportunistas” (CROI, por sus siglas en inglés) llevada a cabo en Boston.

“La HAART en el año 2011 sin duda se tolera mejor que en 1996. Sin embargo, sigue estando asociada con una toxicidad significativa, lo que subraya el hecho de que todavía necesitamos medicamentos mejores o nuevos”, dijo el Dr. Yeni.

La terapia antirretroviral altamente activa es la combinación de al menos tres fármacos antirretrovirales, por lo general dos inhibidores nucleósidos de la transcriptasa inversa (NRTI, por sus siglas en inglés) más un inhibidor de la proteasa, un inhibidor de la integrasa, o un inhibidor de la transcriptasa inversa no análogo de los nucleósidos (NNRTI, por sus siglas en inglés).

Desde su desarrollo en 1996, la seguridad y eficacia de la HAART ha mejorado debido a la disponibilidad de más fármacos activos con menos efectos secundarios y de esquemas de dosificación más sencillos.

Sin embargo, la HAART todavía está asociada con efectos secundarios significativos y no consigue acabar con la mayor parte de la disfunción inmune y la inflamación que se siguen produciendo en las personas con VIH. Con el tiempo, estos problemas pueden conducir a enfermedades cardíacas, enfermedades de los huesos y a una serie de problemas adicionales.

Además, dado que la HAART no cura el VIH, “la terapia antirretroviral es una terapia de por vida”, declaró el Dr. Yeni.

Como resultado, dijo el Dr. Yeni, se necesitan las futuras investigaciones para descubrir nuevos medicamentos antirretrovirales y no antirretrovirales, así como nuevas terapias que podrían curar el VIH.

Nuevos medicamentos antirretrovirales y combinaciones de fármacos

El Dr. Yeni describió varios medicamentos antirretrovirales de nueva y próxima generación que actualmente se encuentran en distintas fases de estudios clínicos.

La mayoría de estas pertenecen a los tipos de medicamentos ya existentes: nuevos NRTIs, inhibidores de la proteasa, NNRTIs e inhibidores de la integrasa. Hay también dos nuevos medicamentos del mismo tipo que el Selzentry (maraviroc), un inhibidor de CCR5, que se encuentran actualmente en estudios clínicos de fase 2.

El Dr. Yeni señaló que algunos de estos nuevos medicamentos presentan ventajas sobre los antirretrovirales aprobados en la actualidad. Por ejemplo, el festinavir es una forma modificada de la estavudina (Zerit) que es 100 veces menos tóxico en las pruebas de laboratorio y por lo tanto podría tener menos efectos secundarios. Está siendo desarrollado por Bristol-Myers Squibb y está en estudios clínicos de fase 2. El CMX-157 y el GS-7340 son versiones modificadas del Viread (tenofovir), que son más activas contra el VIH en pruebas de laboratorio. Ambos medicamentos están aún en estudios clínicos de fase 1.

Además, dos de los fármacos que están en estudios clínicos de fase 2 no pertenecen a los tipos de fármacos existentes. El BMS-663068, desarrollado por Bristol-Myers Squibb, se une a una proteína llamada gp120 en la superficie del VIH. El virus utiliza esta proteína para unirse e infectar a las células inmunes. El Ibalizumab, de Biológicos TaiMed, se une a una proteína en la superficie de las células CD4 (glóbulos blancos). Ambos fármacos evitan que el VIH se adhiera a las células inmunes y las invada.

El Dr. Yeni también debatió acerca de posibles nuevas estrategias para la aplicación de la HAART. En particular, sugirió que en un futuro puede haber cambios en las combinaciones de medicamentos utilizados para la terapia inicial.

En este sentido, se refirió a varias posibilidades, como la inclusión de inhibidores de CCR5 como el Selzentry en los regímenes de tratamiento inicial, la sustitución del tratamiento de base con dos NRTIs por antirretrovirales alternativos, como un NRTI más un inhibidor de la proteasa, e incluso la aplicación de un régimen de medicamentos completamente alternativo, sin ningún tipo de inhibidores de la proteasa o NRTIs, a medida que se desarrollan nuevas clases de fármacos antirretrovirales y los médicos intentan minimizar los efectos secundarios.

El Dr. Yeni también sugirió que en el futuro todo el mundo podría recibir tratamiento justo después de dar positivo en la prueba de VIH. Sólo no empezarían con el tratamiento las personas cuyo sistema inmunológico puede controlar el virus de forma natural sin medicamentos antirretrovirales.

“Bien podría ocurrir que en el futuro la cuestión sobre la iniciación de la terapia antirretroviral pueda [involucrar] la identificación de los pacientes que no deben recibir terapia antirretroviral”, dijo el Dr. Yeni. Sugirió que esto se basaría no sólo en parámetros inmunológicos y virológicos, como la cuenta de CD4 y la carga viral (cantidad de VIH en la sangre), sino también, con el tiempo, en la genética de una persona.

Medicamentos y terapias no antirretrovirales

El Dr. Yeni también habló brevemente sobre las terapias complementarias no antirretrovirales que podrían utilizarse para tratar la disfunción inmune y la inflamación en personas con VIH.

“Estas anomalías están implicadas en la aparición prematura de varias enfermedades, incluidas las [enfermedades] cardiovasculares, el cáncer y la osteoporosis”, dijo el Dr. Yeni.

Destacó varias estrategias para disminuir la inflamación, incluyendo el uso de medicamentos anti-inflamatorios como la aspirina y las estatinas (medicamentos que disminuyen los niveles de colesterol en el cuerpo).

Los científicos también están investigando el uso de una proteína llamada IL-7 para aumentar la función inmunológica en personas con VIH. La IL-7 es una proteína que ayuda a las células inmunes a desarrollarse y sobrevivir.

“Probablemente haya muchos otros enfoques que están siendo investigados en la actualidad”, dijo el Dr. Yeni. También señaló que las estrategias adicionales para hacer frente a la inflamación podrían ser discutidas por el Dr. Tim Schacker, de la Universidad de Minnesota, en una presentación diferente durante el simposio (en inglés).

Para obtener más información, consulte el resumen o la transmisión por Internet en la página web de la CROI 2011 (todos en inglés).

The new guidelines revise a previous version released in December 2009 and contain updated recommendations on several topics, including changes in CD4 (white blood) cell count monitoring, definitions related to viral load (amount of virus in the blood), new drug resistance testing, and recommendations on initial antiretroviral combination regimens. New information is also included on management of coinfection with hepatitis B or tuberculosis.

The guidelines also include a new table listing the most common and/or severe side effects caused by different classes of anti-HIV medications.

Issued by a panel of experts in HIV care and research, the guidelines are intended to aid health care professionals when treating HIV-positive adults and adolescents.

Major changes to the guidelines are outlined below.

CD4 Cell Count Monitoring

The guidelines now recommend that CD4 counts be monitored every 6 to 12 months (instead of every 3 to 6 months) for patients who are on antiretroviral therapy, have achieved viral suppression (amount of virus in the blood of 48 copies per milliliter or less), and whose CD4 cell count is well above the threshold for an increased risk of opportunistic infections.

If changes in the patient’s clinical status occur, such as the start of HIV-associated symptoms or treatment with drugs that can affect the immune system, the guidelines recommend closer monitoring of CD4 counts.

For people who have not yet started antiretroviral therapy or who have recently started treatment, the guidelines still recommend CD4 counts every 3 to 6 months.

Clarification Of Virologic Failure

The new recommendations provide definitions of several terms related to viral loads and virologic failure.

Viral suppression is still defined as an undetectable viral load (less than 48 copies per milliliter). However, due to variability between current viral load assays and the fact that many patients experience small, temporary viral load spikes (“blips”), a patient will only be considered to have virologic failure if they fail to achieve or maintain a viral load of 200 copies per milliliter or less.

In addition, an incomplete virologic response is defined as two consecutive viral load measurements of more than 200 copies per milliliter after 24 weeks of antiretroviral therapy.

Virologic rebound is defined as a confirmed viral load of more than 200 copies per milliliter after previously reaching viral suppression.

Drug Resistance Testing

For drug resistance, the panel now notes that clinicians may want to test for integrase inhibitor resistance if there is concern that resistance may have been transmitted. Standard testing usually only includes testing for resistance against reverse transcriptase inhibitors and protease inhibitors.

The panel also recommends testing for integrase inhibitor resistance in patients who have failed antiretroviral regimens containing an integrase inhibitor, such as Isentress (raltegravir). This can help determine if it is advisable to exclude a drug from this class in subsequent regimens.

Initial Combination Regimens for Treatment-Naive Patients

The new guidelines include important changes in the initial combination regimens recommended for treatment-naïve patients.

The combination of Selzentry (maraviroc) and Combivir (zidovudine/lamivudine) is now listed as an “acceptable regimen,” as the U.S. Food and Drug Administration has now approved Selzentry for use in treatment-naïve patients.

Two additional regimens, including Selzentry in combination with either Truvada (tenofovir/emtricitabine) or Epzicom (abacavir/lamivudine), have been added as “regimens that may be acceptable but more definitive data are needed.”

Due to recent changes to the Invirase (saquinavir) prescribing information as a result of studies linking this medication to significant heart rhythm alterations, Invirase-based regimens boosted with Norvir (ritonavir) have been changed from “alternative protease inhibitor-based regimens” to “regimens that are acceptable but should be used with caution.”

The guidelines also recommend that patients receive an electrocardiogram, a procedure used to diagnose and measure heart rhythm irregularities, before starting Invirase.

Hepatitis B Coinfection

The guidelines recommend that prior to initiation of antiretroviral therapy, all patients who test positive for hepatitis B should undergo further tests to measure their hepatitis B viral load.

If treatment for either hepatitis B or HIV is necessary, the guidelines recommend using either Truvada or a combination of Viread (tenofovir) plus Epivir (lamivudine). These drugs are active against both HIV and hepatitis B infection.

If neither treatment combination is possible, then patients should be treated with Baraclude (entecavir) for hepatitis B plus an antiretroviral regimen that can achieve full viral suppression of HIV.

Tuberculosis Coinfection

The guidelines give new recommendations on when to start antiretroviral therapy in patients with tuberculosis.

The guidelines now state that all HIV-infected patients with diagnosed active tuberculosis should be treated with antiretroviral therapy. The recommended timing of antiretroviral treatment depends on a person’s CD4 count.

• Patients with a CD4 count of less than 200 cells per microliter of blood should start antiretroviral therapy within two to four weeks of starting tuberculosis treatment.
• Patients with a CD4 count of 200 to 500 cells per microliter should start antiretroviral therapy within two to four weeks or by at most eight weeks after starting tuberculosis treatment.
• Patients with a CD4 count of greater than 500 cells per microliter should start antiretroviral therapy within eight weeks of starting tuberculosis treatment.

In addition, for patients taking protease inhibitors, the guidelines recommend that Mycobutin (rifabutin) be used for tuberculosis treatment in order to decrease the risk of drug interactions.

After initiation of antiretroviral therapy and tuberculosis treatment, patients should be monitored for immune reconstitution inflammatory syndrome (IRIS). If IRIS develops, patients should still continue both antiretroviral therapy and tuberculosis treatment.

For more information, please see the Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents (pdf).

Typically, people experience a recovery of their immune system, including an increase in CD4 (white blood cell) count, after starting highly active antiretroviral therapy (HAART). This usually occurs once HAART successfully decreases the amount of virus in the blood (viral load).

However, this is not always the case. In around 10 to 25 percent of patients, CD4 cell counts do not increase even after HIV has been suppressed to undetectable levels with HAART. This is referred to as immunologic failure.

Although there are treatment guidelines for patients in whom HAART fails to suppress the virus, there are no guidelines on what to do when immunologic failure occurs.

Previous studies have suggested protease inhibitors produce greater increases in CD4 count in comparison to other antiretroviral drug classes and have similar viral suppression abilities. However, their ability to raise CD4 counts has not been investigated in patients with immunologic failure.

This study set out to determine if switching to Kaletra (lopinavir/ritonavir), a protease inhibitor, could improve immune recovery in patients suffering from immunologic failure.

A total of 20 patients with immunologic failure after six months or more of HAART were enrolled in the study. HAART usually consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third antiretroviral that is often from a different class, such as a protease inhibitor or integrase inhibitor.

In the study, researchers randomly assigned 10 study participants to stay on their current regimen, while the other 10 kept their current two NRTIs but switched to Kaletra as their third antiretroviral. CD4 cell counts were measured after 1, 3, and 6 months of treatment, then periodically for up to 3 years.

After 6 months, the average increase in CD4 count was 116 cells per microliter of blood for study participants in the Kaletra group versus 32 cells per microliter for those who continued their initial treatment. In addition, more patients in the Kaletra group had a CD4 count increase of more than 50 cells per microliter (7 participants versus 2).

Results also showed that after 3 years, study participants in the Kaletra group continued to see increases in CD4 count, while those who continued their initial treatment regimens saw little overall improvement over time.

One person in the Kaletra group discontinued treatment due to gastrointestinal problems.

Further investigation revealed that the study participants who took Kaletra experienced less of a particular type of cell death, called programmed cell death or apoptosis, in their CD4 cells. Programmed cell death is normally a natural cell process and is different from cell death due to trauma or injury.

People with HIV who experience complete immune recovery have levels of programmed cell death similar to those in HIV-negative people. However, patients with immunologic failure have very high rates of this type of cell death.

Results of this study showed that participants taking Kaletra experienced a decrease of 12 percent in CD4 programmed cell death after six months, whereas participants who continued their current HAART regimens experienced a slight increase in CD4 programmed cell death of 1.6 percent.

The investigators concluded that patients who have immunologic failure after six months or more of effective HAART therapy may benefit from switching to a regimen containing Kaletra, possibly because of its beneficial effects on reducing programmed cell death in CD4 cells.

However, larger studies are needed to confirm these results and further establish the biological mechanisms behind Kaletra’s effects on CD4 counts.

The study was carried out by researchers at the University of Chicago and Abbott Laboratories (the manufacturer of Kaletra).

For more information on the study, please see the article in AIDS Research and Human Retroviruses (pdf).

The guidelines contain updated recommendations in several areas, including diagnosis of HIV in infants, start of antiretroviral therapy, selection of antiretrovirals, and adherence to antiretroviral therapy in children and teenagers.

The guidelines now also include a rating system to indicate the strength of each recommendation, and formatting changes have been implemented to improve readability. For example, a section on drug side effects in children that includes information on risk factors, symptoms, preventative measures, and treatment options is now presented in a table format for ease of use.

The guidelines are intended for use by doctors and other health care professionals when treating HIV-positive children and teens.

Key updates to various sections of the guidelines are summarized below.

Diagnosis Of HIV In Infants

The guidelines now recommend HIV testing at birth for infants who are at high risk for contracting the virus. This includes babies born to HIV-positive mothers who did not receive prenatal care or prenatal antiretroviral therapy, or who had HIV viral loads (amount of virus in the blood) greater than 1,000 copies per milliliter near the time of delivery.

HIV infection in adults is usually diagnosed by looking for antibodies – proteins made by the immune system to help identify and fight bacteria and viruses. In infants, however, tests for HIV antibodies may lead to false-positive results, as children of this age group often still carry their mothers’ HIV antibodies.

To avoid a false diagnosis, the guidelines continue to recommend tests that detect the virus itself to determine HIV status in infants younger than 18 months. This includes HIV DNA PCR assays and HIV RNA tests, both of which can detect the HIV virus directly.

The guide also continues to recommend that babies be tested for HIV at 14 to 21 days after birth, age 1 to 2 months, and 4 to 6 months of age.

Start Of Antiretroviral Therapy

Suggestions for when to initiate antiretroviral therapy vary according to age group.

Antiretroviral therapy is now recommended for children older than 12 months who have normal CD4 (white blood cell) counts but HIV viral loads of 100,000 copies per milliliter of blood or higher, even if their symptoms are mild or nonexistent.

For children under the age of 12 months, the guidelines continue to recommend starting antiretroviral therapy regardless of CD4 count, viral load, or the presence or absence of symptoms. Several studies have shown that starting therapy early in children of this age significantly reduces the chances a child will progress to AIDS or die.

In children with normal CD4 counts whose HIV viral loads are less than 100,000 copies per milliliter, and who have mild or no symptoms, initiation of treatment can be either considered or deferred.

Selection Of Antiretroviral Drugs For Treatment Naïve Patients

As with adults, all HIV-positive children should be treated using combination therapy that includes at least three different antiretroviral drugs from two different classes.

However, the updated guidelines now indicate that non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy is not recommended for children younger than 3 years of age who have been exposed to single dose Viramune (nevirapine).

Viramune is often used to prevent mother-to-child transmission. Babies who have been exposed to Viramune before birth have a higher risk of drug resistance to Viramune after birth. They may also have a higher chance of treatment failure with NNRTI-based antiretroviral therapy.

For children under 3 years of age who have been exposed to Viramune, the preferred treatment is a Kaletra (lopinavir/ritonavir)-based regimen.

In addition, Viramune is not recommended in girls after puberty who have CD4 counts of 250 cells per microliter or higher, and Sustiva (efavirenz) is not recommended in sexually active teenage girls unless contraception can be reliably guaranteed.

Other antiretrovirals that are not recommended are Viracept (nelfinavir) for children under 2 years of age, Sustiva in children under 3 years of age, and unboosted Prezista (darunavir), Invirase (saquinavir mesylate), or Aptivus (tipranavir).

Drugs that should not be combined in children include Epivir (lamivudine) plus Emtriva (emtricitabine), zidovudine (Retrovir) plus stavudine (Zerit), or dual NNRTI regimens.

The guidelines also recommend against once daily (rather than twice daily) dosing of Kaletra, boosted Prezista, and boosted or unboosted Lexiva (fosamprenavir) in children. Although once-daily doses of these antiretrovirals have been approved in adults, the effectiveness of once-daily dosing versus twice-daily dosing has not been shown in children.

The guide continues to recommend that treatment naïve patients (patients who have never received antiretroviral therapy) complete antiretroviral drug resistance testing before choosing which drugs to use for treatment.

Adherence To Antiretroviral Therapy

Adherence to therapy can often be difficult for children and teenagers. Ensuring that patients follow their treatment regimens is important because missing doses can cause HIV to develop resistance to treatment, leading to treatment failure.

The guidelines now recommend that at least one method to monitor adherence, such as self-reporting of missed doses or pharmacy refill checks, be used in addition to viral load tests.

The updated guidelines also suggest prescribing once-daily antiretroviral therapy when possible rather than twice-daily dosing, since studies in adults have shown once-daily dosages promote better adherence.

For more information, please see the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (pdf).

People with HIV are more prone to kidney disease, both because of the HIV virus, which can infect and kill kidney cells, and from damage caused by the antiretrovirals used to treat it. Viread (tenofovir), in particular, has been associated with loss of kidney function.

Viread is commonly used in combination with other antiretroviral medications and is an ingredient in Atripla (efavirenz/emtricitabine/tenofovir) and Truvada (emtricitabine/tenofovir).

Norvir (ritonavir) has also been linked to kidney problems, though less frequently than Viread. Norvir is commonly used as a “booster” to enhance the effectiveness of protease inhibitor treatment regimens. Norvir is also an ingredient in Kaletra (lopinavir/ritonavir).

In these studies, researchers continued to look for risk factors, including the use of antiretrovirals, that are associated with development of kidney disease in people with HIV.

Treatment With Viread Alone And In Combination With Other Drugs Is Associated With Decreased Kidney Function

A large study that reviewed medical records for over 5,600 HIV-positive patients confirmed that taking Viread is associated with a significant risk of kidney disease.

Researchers found that about 6 percent of the patients taking Viread developed kidney impairment, with 60 percent of those patients experiencing a 50 percent or greater loss of kidney function.

The researchers also found that the greatest predictor of decreasing kidney function was the number of months taking Viread, with longer Viread treatment associated with greater risk of kidney problems.

A second study found that treatment with Viread was associated with a greater decrease in kidney function compared to regimens without Viread.

The study measured kidney function in 474 HIV-positive adults treated with a variety of antiretroviral regimens, some with Viread and some without. Prior to the study, none of the participants had received treatment for their HIV.

Changes in kidney function were observed over a period of 96 weeks.

Combined, participants treated with Viread-containing regimens had declines in kidney function that were about three-fold larger than patients on non-Viread antiretroviral regimens.

Additionally, a greater decline in kidney function was observed in participants treated with Viread plus Kaletra compared to patients treated with Viread plus Sustiva (efavirenz).

Kaletra inhibits the breakdown of Viread in the body, which means people taking Kaletra plus Viread may have higher amounts of Viread in their system for a longer period of time. Sustiva does not affect the rate of Viread breakdown in the body.

Results of both studies emphasize the importance of carefully monitoring kidney function in patients receiving Viread therapy.

Advancing Age And Treatment With Norvir Are Associated With Kidney Disease

An ongoing Brazilian study has found that the use of Norvir, with or without Viread, is also associated with kidney disease.

The study has included 196 participants so far, all of whom have taken antiretroviral therapy for at least a year and have achieved viral suppression, 50 copies of HIV per milliliter or less.

Researchers classified each participant as having either normal kidney function (62 percent) or mild, moderate, or severe kidney impairment (29 percent, 8 percent, and 1 percent, respectively).

Results showed that moderate or severe kidney impairment was associated with taking Norvir (with or without Viread) and increasing age. European ancestry was also related to poorer kidney function.

However, the researchers noted that the results were still preliminary and more study participants would be needed to confirm these results.

In another study, Italian researchers found that older age, treatment with protease inhibitors boosted with Norvir, and smaller gains in CD4 (white blood cell) count after starting antiretroviral therapy are risk factors for kidney disease in people with HIV.

The study included 590 HIV-positive participants who were starting antiretroviral therapy for the first time.

Results showed that being more than 55 years old and having a more advanced HIV infection were also linked to a greater risk of kidney problems.

Unlike in previous studies, the researchers did not find treatment with Viread to be associated with a greater risk of kidney failure.

For more information, please see the AIDS 2010 conference website.

“The rate of [brain] impairment in patients with HIV is much, much higher” than in the general population, said Dr. Valcour, a physician at the Memory and Aging Center at the University of California in San Francisco, where he is also an Associate Professor in geriatric medicine and neurology.

“About half of patients who have HIV will have abnormal [brain] testing,” he said.

HIV is known to cause damage to the brain that can lead to impairment or, in severe cases, dementia. Brain impairment can involve loss of memory, motor skills, and concentration abilities, as well as behavioral changes and general mental slowness.

Before the advent of highly active antiretroviral therapy (HAART), HIV-associated dementia – the most severe form of HIV-related brain impairment – was fairly common, affecting up to half of people who died of AIDS.

Today, according to Dr. Valcour, “HIV-associated dementia is now quite rare.” However, rates of milder forms of brain impairment have not decreased with HAART and still affect around half of people with HIV.

In many cases, patients may not even realize their brains have been affected, since symptoms may be unnoticeable without specialized testing.

Although the cause of HIV-related brain impairment is not yet known, Dr. Valcour argued that it is an active disease process that continues even when patients are on HAART. This is in contrast to the theory that the impairment is a delayed consequence of damage from earlier in the infection, before treatment begins.

More specifically, Dr. Valcour believes the problem has to do with latent HIV – HIV that remains hidden within the body and is not eliminated by antiretrovirals. Patients who get dementia appear to have higher levels of this latent HIV in their system, even after years of HAART.

The high levels of latent HIV mean that some cells, including immune cells that cross into the brain, still have HIV in them, which may be causing some of the damage to brain cells.

“I think our work is cut out for us to try to figure out ways in which we can attack these [latent HIV] reservoirs and try to clear them, perhaps causing some benefit for [brain] impairment,” said Dr. Valcour.

“We are inadequately treating [brain impairment] with the existing regimens that we have,” he added.

He pointed out that not all antiretroviral drugs are equally effective at reaching HIV in the brain.

“The higher the brain penetration effectiveness of your overall antiretroviral regimen, the more likely you are to have undetectable virus in your CSF [cerebrospinal fluid],” he said. CSF is the fluid that surrounds the brain and spinal cord.

Dr. Valcour finished his talk by stating that work still needs to be done to improve screening and identification of patients affected by brain impairment.

The current specialized tests for determining brain impairment are too complicated and time-consuming to do for everyone, he said, so better screening tools are needed to effectively diagnose minor brain impairment in people with HIV. Ideally, everyone with HIV would then get tested for brain problems.

“If 50 percent of patients who came into your clinic could have a disease, wouldn’t you want to screen everyone? It is a feasibility issue. I think we need to figure out a way to make this work,” he said.

Dr. Valcour also stressed the importance of remaining fit and healthy.

“Things that you as patients can do and you as doctors can recommend: stop smoking, get exercise, treat diseases when they present, [and] be very aggressive about treating depression and psychiatric illness,” he said.

“Patients should remain physically and cognitively stimulated. Physical exercise I think cannot be overstated,” added Dr. Valcour.

For more information, please see the AIDS 2010 webpage on the Kaiser Family Foundation website.