In addition, the companies are currently in negotiations to develop a second pill combining Prezista, cobicistat, Emtriva, and an investigational new form of Viread called GS 7340.

“We are excited to be able to study and develop Prezista with an alternative boosting agent in a combination product which has the potential to reduce the number of tablets patients take,” said Dr. Johan Van Hoof, area head of Global Therapeutics for Infectious Diseases and Vaccines at Janssen Pharmaceutica (Tibotec’s parent company), in a press release.

Prezista (darunavir) is currently listed as a preferred protease inhibitor for first-line antiretroviral regimens for people with HIV. Cobicistat is under development by Gilead as a boosting agent similar to Norvir (ritonavir) and is in Phase 3 clinical trials. Gilead expects to file a New Drug Application for cobicistat with the U.S. Food and Drug Administration (FDA) in mid-2012.

The new combination pill would be the second once-daily protease inhibitor pill that combines an antiretroviral with a boosting agent; the other is Abbott Laboratories’ Kaletra (lopinavir/ritonavir). All other protease inhibitors must currently be taken with Norvir as a separate pill.

According to the agreement, the Prezista plus cobicistat combination will be developed and marketed by Tibotec, which is also responsible for filing a New Drug Application for the pill.

The companies stated that the agreement to develop a Prezista plus cobicistat combination pill is contingent on signing a second agreement to create a once-daily combination of Prezista, cobicistat, Emtriva (emtricitabine), and GS 7340. GS 7340, which is still in Phase 1 clinical trials, is a new formulation of Viread (tenofovir) that is expected to be safer and more effective than the current version.

If the agreement is signed, Gilead will be responsible for developing and marketing the second combination pill.

Tibotec and Gilead are also in the process of developing a once-daily combination pill that contains Truvada (tenofovir/emtricitabine) plus Edurant (rilpivirine), Tibotec’s new non-nucleoside reverse transcriptase inhibitor. Edurant was approved by the FDA in May (see related AIDS Beacon news). Tibotec expects the new combination pill to be available in the third quarter of this year.

For more information, please see the press releases from Gilead and Tibotec (pdf).

AIDSinfo Releases Adult And Adolescent Antiretroviral Guidelines In Web-Friendly Format – AIDSinfo, a website run by the U.S. Department of Health and Human Services, now offers a way to view the latest antiretroviral guidelines for adults and adolescents in both web-friendly and printer-friendly formats.  Pediatric and other HIV-related guidelines are available on the site in a printer-friendly format. For more information, please visit the AIDSinfo website.

Phase 3 Clinical Trial Tests Truvada Plus Rilpivirine Combination Pill Versus Atripla In Previously Untreated HIV-Positive Adults – Gilead Sciences is currently recruiting participants for a Phase 3 study testing the efficacy and safety of a single tablet regimen of Truvada (emtricitabine/ tenofovir) plus rilpivirine (TMC278) compared to Atripla (efavirenz/emtricitabine/tenofovir).  HIV-positive adults who have not been previously treated with antiretroviral therapy may be eligible. Participants will receive either a once-daily tablet of Truvada/rilpivirine or Atripla for 96 weeks. At 48 weeks, viral load (amount of HIV RNA) and CD4 (white blood) cell counts will be assessed.  At 96 weeks, CD4 cell counts will be reassessed. For more information, please visit the U.S. Clinical Trials Registry.

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 study results support the findings from previous shorter-term studies showing that treatment interruptions are highly detrimental to people with HIV.

Based on these findings, the researchers suggested that doctors initiate antiretroviral therapy early in HIV patients, avoid treatment interruptions or keep them as short as possible, and decrease viral loads as much as possible.

Antiretroviral therapy consists of at least three antiretroviral drugs to stop the progression of HIV infection. Antiretroviral regimens promote recovery of CD4 (white blood) cells, decrease viral load (amount of virus in the blood), and increase life expectancy.

However, antiretroviral therapy is frequently interrupted or discontinued by HIV patients because of side effects, inconvenience, or psychological factors such as depression.

Previous studies have indicated that treatment interruptions are more likely to lead to HIV-associated illnesses and death. However, these studies did not evaluate longer-term consequences of treatment interruption.

In this study, researchers evaluated CD4 cell recovery, number of opportunistic infections, and mortality in 2,491 HIV patients for an average of seven years to evaluate longer-term consequences of treatment interruption.

All study participants started a treatment regimen of at least three antiretroviral drugs. Based on participants’ response to treatment and whether or not they ever discontinued therapy, researchers categorized them into three groups.

The first group consisted of participants who had discontinued treatment for at least one month during the study period. The second group included participants who had no treatment interruptions but were unable to achieve a consistent viral load below 1,000 copies per milliliter. The third group consisted of patients who had no treatment interruptions and consistently had viral loads under 1,000 copies per milliliter starting six months after beginning treatment.

Results showed that patients with interruptions in treatment had poorer CD4 cell recovery, more opportunistic infections and HIV-related illnesses, and a slightly higher mortality rate.

After eight years of treatment, 63 percent of patients with interruptions in therapy achieved a CD4 count threshold of more than 350 cells per microliter of blood, compared to 76 percent and 87 percent of participants in the two groups with no treatment interruptions.

In addition, only 37 percent of patients with treatment interruptions reached a CD4 count of more than 500 cells per microliter of blood, compared to 56 percent and 68 percent of patients undergoing continuous treatment.

Poorer CD4 cell recovery was also associated with older age and hepatitis C co-infection.

The researchers also observed that the duration of treatment interruptions had an effect on CD4 recovery. Discontinuing antiretroviral therapy for three months or more resulted in smaller increases in CD4 counts after eight years of treatment compared to continuous therapy. Interruptions lasting for more than 31 months resulted in CD4 decline.

More participants with treatment interruptions (10.5 percent) experienced opportunistic infections and HIV-related illnesses such as shingles, Candida (fungal) infections, and non-Hodgkin’s lymphoma than participants in the two groups with no treatment interruptions (6.1 percent and 4.5 percent, respectively).

Longer durations of treatment discontinuation resulted in higher rates of new opportunistic infections. Fourteen percent of participants who discontinued treatment for 15 months or more had a serious HIV-related illness, compared to 6 percent of participants with treatment discontinuations of a month or less.

The researchers observed a slightly higher HIV-related death rate in patients with treatment interruptions compared to people with no interruptions and successful viral control. Participants with no interruptions but inconsistent viral control had a similar HIV-related death rate as people with treatment interruptions.

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

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).

The Pharmaceutical Research and Manufacturers of America (PhRMA), a pharmaceutical company lobbying group, releases a report each year on HIV treatments under development at U.S. pharmaceutical companies. The report this year includes new antiretrovirals, gene therapies, and vaccine candidates, in addition to treatments for HIV-related conditions such as Kaposi’s sarcoma and peripheral neuropathy (pain or numbness in the extremities).

Most of the new antiretrovirals are still in Phase 1 or Phase 2 clinical trials. The list includes novel drug types that work differently than current anti-HIV drugs, as well as drugs in standard antiretroviral drug classes, such as new protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs).

In addition, there are three new combination treatments under development. Combination treatments include several antiretrovirals in one pill, which simplifies treatment regimens.

New Types Of Antiretroviral Drugs

Several of the antiretrovirals in the report are novel drug types that are not part of existing antiretroviral drug classes.

A number of these treatments consist of antibodies, proteins that help the body recognize and fight viruses. These treatments usually work by attempting to stimulate the immune system so that it can more effectively recognize and kill HIV or infected cells. Nearly all of these are still in Phase 1 clinical trials, although one set of antibodies are in Phase 2 trials.

There are a few additional prospective drugs that have made it to Phase 2 trials. One of these is also a protein treatment, called Alferon LDO (interferon alfa-n3). This protein is isolated from human blood and helps fight viral infections; currently it is approved by the U.S. Food and Drug Administration to fight human papillomavirus, which causes genital warts.

Another new treatment, called CB1922, is currently in Phase 2 clinical trials. CB1922 is a drug that has mostly been investigated for treatment of high blood pressure. It works by blocking a protein on the surface of cells that normally binds to a hormone called aldosterone.

Canopus BioPharma, which makes CB1922, has found that HIV also binds to this same protein by mimicking the hormone. By blocking the protein, CB1922 appears to prevent HIV from replicating itself.

Finally, a drug from Bristol-Myers Squibb, called BMS-626529, is also in Phase 2 clinical trials. Bristol-Myers Squibb has not explained the mechanism of BMS-626529, but states that it prevents HIV from attaching to cells, which would prevent infection and virus replication.

New Drugs In Existing Antiretroviral Drug Classes

Most of the new drug candidates are in existing antiretroviral drug classes, including the following two drugs that are in or have completed Phase 3 trials: elvitegravir, which is a new integrase inhibitor from Gilead Sciences, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Tibotec Pharmaceuticals.

Integrase inhibitors, such as elvitegravir, are a relatively new class of antiretroviral; currently, the only approved integrase inhibitor is Isentress (raltegravir).

In addition to elvitegravir, there are three new integrase inhibitors under development (GSK1247303, GSK1265744, and GSK1349672). All of these are in Phase 2 clinical trials and were developed by GlaxoSmithKline.

NNRTIs, in contrast, are an older drug class that includes Sustiva (efavirenz), Viramune (nevirapine), and Intelence (etravirine). Including rilpivirine, there are seven new NNRTIs under development; four of these are also in Phase 2 clinical trials (dapivirine vaginal gel, RDEA806, UK-453061, and VRX806).

The list includes seven new NRTIs, which is the oldest antiretroviral drug class and includes drugs such as zidovudine (Retrovir) and Epivir (lamivudine). Four of the proposed new NRTIs (elvucitabine, festinavir, racivir, and amdoxovir) are in Phase 2 clinical trials.

Only two new protease inhibitors (a drug class that includes Prezista (darunavir) and Kaletra (lopinavir/ritonavir)) were included in the report, one of which, TMC310911, is in Phase 2 trials.

Finally, the report includes several new entry inhibitors, which are another fairly new class of antiretroviral that includes the drugs Selzentry (maraviroc) and Fuzeon (enfuvirtide).

Entry inhibitors work by preventing HIV from entering and infecting new cells. Most of the new treatments act the same way as Selzentry, which blocks a protein called CCR5 on the surface of white blood cells that HIV uses to attach to and invade. Two of the proposed new entry inhibitors (PRO-140 and TBR-652) are in Phase 2 clinical trials.

New Combination Drugs

Combining several antiretroviral drugs into one pill has been a growing trend, since it simplifies antiretroviral regimens for patients. There are currently three combination treatments under development.

One, called the “Quad” pill (see related AIDS Beacon news), is a combination of four drugs in one pill: Emtriva (emtricitabine), Viread (tenofovir), and the investigational integrase inhibitor elvitegravir plus a proposed new antiretroviral booster, cobicistat. Cobicistat is thought to act similarly to Norvir (ritonavir) by raising antiretroviral drug concentrations to make them more effective.

A second combination pill will include the new NNRTI rilpivirine plus Emtriva and Viread.

Finally, the third proposed combination pill will include three already approved antiretrovirals: Sustiva (efavirenz), Epivir (lamivudine), and Viread.

Gene Therapy And Vaccines

Aside from antiretroviral drugs, the report includes both gene therapies and therapeutic vaccine treatments as potential new HIV treatments.

Gene therapy treatments are experimental procedures that scientists hope will one day be able to cure HIV (see related AIDS Beacon news). They work by changing a person’s genes, for example by turning off genes that produce proteins used by HIV to infect cells.

Three gene therapy treatments are currently under development, two of them in Phase 1 trials and one in Phase 2.

Two of the treatments work by inserting genes that make genetic material that binds to and neutralizes HIV’s genetic material so that it no longer functions. One of the treatments is being developed by the biotechnology company VIRxSYS and is currently in Phase 1 trials. The second one by Enzo Biochem is currently in Phase 2 trials.

The third therapy, by Sangamo Biosciences, works by preventing cells from producing the CCR5 protein on their surface, preventing HIV from infecting the cells in much the same way Selzentry does.

Finally, there are a number of therapeutic vaccines also under development (see related AIDS Beacon news). Therapeutic vaccines enhance the body’s natural immune response, helping to control HIV in people already infected with the virus.

Most of the therapeutic vaccines are in Phase 1 clinical trials. However, there are a few that are in Phase 2.

One of these is a dendritic cell vaccine by Argos Therapeutics. Dendritic cell vaccines are made by collecting blood from patients and isolating a certain type of immune cell called a dendritic cell.

After exposing the dendritic cells to HIV proteins in the laboratory to prompt an immune response, the cells are reinjected into the study participant in hopes that the cells will now be activated and fight against HIV.

Two other therapeutic vaccines that are in Phase 2 clinical trials are the DermaVir vaccine, by the company Genetic Immunity, and Vacc-4x by Bionor Pharma (see related AIDS Beacon news).

The DermaVir vaccine is applied as a patch rather than an injection and attempts to limit virus replication. Vacc-4x, in contrast, contains protein fragments similar to those found within the HIV virus, in an attempt to enhance the ability of patients’ immune systems to recognize and kill HIV-infected cells.

For more information, please see the report from PhRMA. For more information on clinical trials, please see the United States Clinical Trials Registry.

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 inability to normalize CD4 counts among many patients starting antiretroviral therapy at low CD4 counts, even after 7 years of treatment, provides additional support to consider initiation of therapy at higher CD4 counts,” said Professor Judith Lok, lead author on the study, in correspondence with The AIDS Beacon.

When to begin antiretroviral therapy is currently a subject of disagreement among doctors, scientists, and AIDS activists (see related AIDS Beacon news).

Current guidelines suggest initiating treatment when a person’s CD4 (white blood cell) count is 350 cells per microliter of blood or less. However, a growing body of evidence suggests that starting treatment earlier may be able to prevent irreversible immune system damage (see related AIDS Beacon news).

To evaluate the existing treatment-initiation guidelines, researchers in this study compared people who started HIV treatment at higher CD4 counts to those who started at low CD4 counts. In particular, they examined whether participants’ CD4 counts increased over time once they began taking antiretroviral medications, and if so, how much.

The study monitored 575 HIV-positive participants from the time they first started antiretroviral medications. Researchers recorded the participants’ CD4 cell counts before beginning antiretroviral therapy and at 3 years and 7 years after starting treatment.

Results showed that after 3 years the median CD4 count among all study participants increased from 270 to 556 cells per microliter. After 7 years results were similar, with a slightly lower median CD4 count of 532 cells per microliter of blood.

The researchers hypothesized that the slight drop after 3 years was due to the fact that some participants stopped antiretroviral treatment when their CD4 counts increased, a practice which is no longer recommended. If all study participants had continued to take antiretrovirals, the researchers estimated that CD4 counts would have continued to increase during the entire 7 year period.

Results also showed that CD4 counts 7 years after starting antiretroviral therapy were highly dependent on initial CD4 counts. Study participants who started with CD4 counts above 500 cells per microliter had a final median CD4 count of 724 cells per microliter. Participants whose initial CD4 counts were less than 200 cells per microliter had a final median CD4 count of 453 cells per microliter.

Participants who started antiretroviral therapy at CD4 counts of 200 or less were also four times more likely to have CD4 counts under 350 or to have died at the end of the 7 year period than participants who started at CD4 counts of 500 or more.

The study authors suggested this may indicate irreversible immune system damage in people who wait to start antiretroviral therapy.

“I believe the immune system gets exhausted and eventually loses the reserve needed to fully rebound,” said Dr. Gregory Robbins, another author on the study, in correspondence with The AIDS Beacon.

“It is possible that the damage to the immune system in patients with low CD4 counts might not be easy to repair even if treatment with antiretroviral therapy is given,” added Professor Lok.

The researchers concluded that the CD4 counts of most patients using antiretrovirals increase for at least 7 years after treatment initiation. However, they also suggested that antiretroviral therapy is less effective at increasing long-term CD4 counts when it is begun at lower CD4 counts.

Dr. Robbins stated that the results do not indicate a specific CD4 count at which patients should start antiretroviral therapy. “I don’t believe there’s a magic number, and these studies can only give guidance as to when to start,” he said.

“As a clinician, I think thresholds can only be guidelines, as patients’ willingness to start is often the bigger issue,” he added.

A clinical trial testing the effects of starting antiretroviral therapy when a person’s CD4 count drops below 500 cells per microliter is currently underway.

The study, named Strategic Timing of Antiretroviral Treatment (START), is a joint effort by the University of Minnesota, the National Institutes of Health, various European HIV institutes, and several pharmaceutical companies.

The study is currently recruiting participants.

For more information, please see the study in AIDS (abstract). For more details on the START study, please see the clinical description at the United States Clinical Trials registry.

“There seems to be a biological difference if one starts treatment during primary infection when compared to chronic infection,” said Dr. Huldrych Günthard, co-author of the study, in correspondence with The AIDS Beacon. “What these findings mean in the long-run we do not know yet.”

“In general, it supports the recent shift in starting treatment earlier,” he added.

During the early stages of HIV infection, HIV replicates rapidly and many immune cells are infected with the virus. This “acute” stage usually lasts several weeks to a few months; then the chronic stage of HIV infection, which can last years or even decades, begins.

When a person with HIV starts antiretroviral therapy – often during the chronic phase of HIV infection – the amount of HIV circulating in the blood usually drops to undetectable levels. However, some cells remain infected with latent HIV – HIV that lies dormant and can start multiplying again if antiretroviral therapy is stopped. Current antiretrovirals cannot get rid of latent HIV.

Some scientists have speculated that this latent HIV may be partly responsible for some of the long-term damage that is caused by the virus even in people who have taken antiretrovirals for many years (see related AIDS Beacon news).

Some research has suggested that antiretroviral therapy initiated in the acute phase of HIV infection may help limit the size of this latent reservoir. However, results have been conflicting.

In this study, researchers sought to further understand the possible benefits of early antiretroviral therapy by monitoring the amount of HIV RNA in blood cells. RNA is part of the virus’ genetic material and is similar to DNA; scientists measure the amount of latent HIV in a person by measuring the levels of HIV RNA in their cells.

The study enrolled 24 acutely infected HIV patients, who were treated with antiretrovirals within 3 to 15 weeks of initial infection. The study also included 15 people with chronic HIV infections.

The researchers measured the amount of HIV RNA being produced in the participants’ blood immune cells after they started antiretroviral therapy.

Results showed that the acute infection group appeared to have a much smaller latent HIV reservoir while taking antiretrovirals. RNA levels were undetectable in 58 percent of acutely infected participants, compared to 13 percent of chronically infected participants taking antiretrovirals.

In addition, the RNA levels were an average of 100 times lower in the acute infection group than in the chronic infection group.

The findings support the idea that acutely infected patients who begin antiretroviral therapy early on may be able to limit the size of their latent HIV reservoir.

It is not clear, however, whether the results lasted once participants discontinued their antiretroviral therapy regimen. In the acutely-infected participants, the amount of virus RNA measured after stopping antiretrovirals was lower than before starting therapy, but not enough to be considered statistically significant.

Nonetheless, the results are promising for people who manage to detect their HIV infections early.

“The unprecedented finding that residual viral transcription was almost completely depleted suggests that the latent reservoir of HIV-1 during cART [combination antiretroviral therapy] can be reduced by early intervention,” said Dr. Günthard.

“Proof of concept studies aiming at HIV-1 eradication or remission of HIV-1 replication should be initiated in patients during acute infection,” he added.

For more information, please see the study in PLoS One.