“The most important message from the study is that dolutegravir is a safe and highly potent drug which can be given at low doses without a pharmacologic booster once daily,”  said Dr. Jan van Lunzen, a professor at the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany and lead author of the study.

“Thus it has the potential to be a very attractive future component of combination antiretroviral therapy, both in antiretroviral-naïve as well as experienced patients,” he added.

Patients receiving dolutegravir also showed a more rapid decrease in viral load (amount of HIV in the blood) compared to patients receiving Sustiva. The decrease was maintained through week 48 of the study, and the rate of decrease was similar to that reported for the integrase inhibitor Isentress.

The investigators noted that this might have important implications for people with HIV who require an especially rapid reduction in viral load, for example, late-presenting pregnant women with HIV.

The investigators stated that based on their results, they selected the once-daily 50 mg dose of dolutegravir, the highest well-tolerated dose studied, for further testing in Phase 3 trials.

“Currently there are three Phase 3 studies underway in treatment-naïve populations comparing dolutegravir with either efavirenz [Sustiva], darunavir/r [Norvir-boosted Prezista], or raltegravir [Isentress]. Another Phase 3 trial is currently ongoing in experienced patients with previous treatment failure,” said Dr. van Lunzen.

The interim results after 48 weeks were first presented at the 6^th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (see related AIDS Beacon news),

Dolutegravir (S/GSK1349572) is a potential new integrase inhibitor being developed by ViiV Healthcare, a joint venture by GlaxoSmithKline and Pfizer.

Currently, the only approved integrase inhibitor is Isentress (raltegravir), which is marketed by the United States pharmaceutical company Merck. Isentress must be taken twice-daily in combination with other antiretrovirals as part of highly active antiretroviral therapy.

In recent years, the U.S. Food and Drug Administration has approved once-daily rather than twice-daily dosages of several antiretrovirals. Previous research has shown that once-daily dosing is more convenient and promotes better adherence to drug regimens. Better adherence allows for slower disease progression and helps prevent the development of drug-resistant HIV strains.

However, results from a recent study showed that Isentress once daily is not as effective as twice daily (see related AIDS Beacon news). Elvitegravir, which is another investigational integrase inhibitor that is currently in Phase 3 clinical trials, is given once daily but must be taken with a booster such as Norvir (ritonavir) or cobicistat.

According to the study authors, previous studies of dolutegravir in people have shown it to be long lasting without the need for a booster. Results of another ongoing study also indicate that dolutegravir is effective against viral strains resistant to both Isentress and elvitegravir.

The 96 week-long Phase 2 trial was designed to test the safety and efficacy of several once-daily dolutegravir dosages relative to Sustiva (efavirenz). Sustiva, when combined with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen to treat HIV.

A total of 205 previously untreated HIV-positive adults were randomly assigned to receive 10 mg, 25 mg, or 50 mg dolutegravir, or 600 mg Sustiva. Patients in each group also took either Truvada or Epzicom (abacavir/lamivudine).

Results showed that after 16 weeks, about 93 percent of patients in all dosage groups of dolutegravir had undetectable viral loads, with little difference between the dose groups. Sixty percent of participants taking Sustiva had undetectable viral loads.

After 48 weeks, 91 percent, 88 percent, and 90 percent of participants in the dolutegravir groups, respectively, and 82 percent of the participants in the Sustiva group had successfully achieved undetectable viral loads.

In addition, CD4 (white blood cell) counts increased in all three dolutegravir groups and in the Sustiva group through week 48. Average increases were larger in the dolutegravir group, 231 cells per microliter versus 174 cells per microliter in the Sustiva group.

Nearly half of participants (46 percent) experienced one or more drug-related side effects during the first 48 weeks of the study, but investigators concluded that no serious side effects were related to dolutegravir. More participants in the Sustiva group had moderate or severe drug-related side effects (20 percent, compared with 8 percent in the dolutegravir groups).

The most common side effects in participants taking dolutegravir were nausea (12 percent of participants), diarrhea (8 percent), headache (6 percent), dizziness (3 percent), fatigue (3 percent), and weakness (3 percent).

Six participants withdrew from the study: one each in the 25 mg and 50 mg dolutegravir groups due to upset stomach/indigestion and lymphatic cancer, respectively, and four in the Sustiva group due to drug intolerance, drug sensitivity, abnormal dreams, and suicide attempt.

Investigators did not identify any HIV integrase mutations in patients in the study.

For more information, please see the study in The Lancet Infectious Diseases (abstract).

In addition, participants taking Isentress (raltegravir) reported fewer side effects than participants taking Sustiva (efavirenz).

“These results offer further insight into the virologic and immunologic response seen with Isentress in combination therapy when compared to [Sustiva] at 192 weeks in treatment-naïve adult patients with HIV-1,” said Dr. Jürgen Rockstroh, a professor of medicine at the University of Bonn in Bonn-Venusberg, Germany, in a press release. Dr. Rockstroh presented the results yesterday at the European AIDS Conference (EACS) in Belgrade, Serbia.

U.S. pharmaceutical company Merck, which sponsored the trial, released results in July from a Phase 2 clinical trial that also showed similar long-term safety and efficacy of Isentress compared to Sustiva (see related AIDS Beacon news).

The antiretroviral Isentress is approved both for treatment-experienced adults with HIV and as a first-line treatment for people who have not previously taken antiretrovirals. Isentress is currently the only approved integrase inhibitor, although two other investigational integrase inhibitors – dolutegravir and elvitegravir – are in Phase 3 clinical trials.

Sustiva, which is a non-nucleoside reverse transcriptase inhibitor, is often combined with Truvada (emtricitabine/tenofovir)  in the form of Atripla (efavirenz/emtricitabine/tenofovir). Atripla is the most commonly prescribed first-line regimen for people with HIV.

Both Sustiva and Isentress, in combination with Truvada, are listed in HIV treatment guidelines as “preferred” regimens for people starting antiretroviral therapy for the first time.

In this study, researchers are comparing the long-term safety and efficacy of Isentress and Sustiva.

The study includes 563 previously untreated HIV-positive adults. Participants were randomly assigned to take either Sustiva once daily or Isentress twice daily, both in combination with Truvada.

Results after 192 weeks (about three and a half years) show that 76 percent of participants taking Isentress have successfully achieved and maintained undetectable viral loads (amount of HIV in the blood), compared to 67 percent of participants taking Sustiva.

In addition, participants taking Isentress have had an average increase in CD4 (white blood cell) counts of 361 cells per microliter over this period, versus an average increase of 301 cells per microliter in participants taking Sustiva.

Fewer patients taking Isentress reported side effects (50 percent) than those taking Sustiva (80 percent), although the rate of serious side effects was similar for the two groups (18 percent).

Overall, 5 percent of participants taking Isentress and 8 percent of participants taking Sustiva discontinued the drugs due to side effects.

For more information, please see the Merck press release.

“La lersivirina pertenece a la nueva generación de inhibidores no nucleósidos de la transcriptasa inversa … [que] tiene una actividad potente contra el VIH”, dijo el Dr. Anton Pozniak, que presentó los resultados en la 6ª Conferencia Internacional de la Sociedad del SIDA sobre Patogénesis, Tratamiento y Prevención del VIH (IAS 2011).
“Las dos dosis de lersivirina [probadas] lograron una supresión de la carga viral similar a [Sustiva]”, añadió.

El Dr. Pozniak sugirió que la lersivirina también podría ser una opción para la gente que es resistente a la Sustiva (efavirenz), ya que los dos fármacos funcionan de forma ligeramente diferente. Sin embargo, señaló que los resultados necesitan confirmarse en un estudio clínico de fase 3 más grande.

La lersivirina (UK-453061) es un nuevo y potente inhibidor no nucleósido de la transcriptasa inversa (NNRTI, por sus siglas en inglés), que ViiV Healthcare, una empresa conjunta de GlaxoSmithKline y Pfizer, está desarrollando.

El estudio clínico en fase 2b se diseñó para evaluar la seguridad y la eficacia de la lersivirina frente a la Sustiva, que también es un NNRTI. Ambos antirretrovirales se toman en combinación con Truvada (emtricitabina/tenofovir). La Sustiva más la Truvada equivalen a la Atripla (efavirenz/emtricitabina/tenofovir), el tratamiento de primera línea prescrito con mayor frecuencia a las personas con VIH en los Estados Unidos.

El estudio incluye a 193 participantes con VIH que no habían recibido tratamiento con antirretrovirales antes de comenzar el estudio. Se asignó de manera aleatoria a los participantes a los siguientes grupos de tratramiento: 500 mg de lersivirina una vez al día más Truvada (65 participantes), 750 mg de lersivirina una vez al día más Truvada (65 participantes), o Sustiva más Truvada (63 participantes).

Los resultados demuestran que, transcurridas 48 semanas, el 79 por ciento de los participantes que tomaron lersivirina había alcanzado una carga viral (cantidad de VIH en sangre) indetectable  en comparación con el 86 por ciento de los participantes que tomaron Sustiva. La diferencia de eficacia entre los dos fármacos no es lo suficientemente grande como para considerarse significativa.

Los tres grupos experimentaron aumentos similares en la cuenta de CD4 (globulos blancos en la sangre), de 191, 195 y 188 células por microlitro en los grupos que tomaron 500 o 750 mg de lersivirina, y en  el grupo que tomó Sustiva, respectivamente.

Los efectos secundarios adversos de la  lersivirina fueron diferentes a los de la Sustiva. Los efectos secundarios más comunes en los grupos que tomaron lersivirina fueron náuseas (23 y 42 por ciento en los grupos que tomaron 500 y 750 mg, respectivamente) y dolor de cabeza (23 y 17 por ciento en los grupos que tomaron 500 y 750 mg, respectivamente). Los efectos secundarios más comunes en el grupo que tomó Sustiva fueron sueños extraños (19 por ciento) y mareos (21 por ciento).

Los efectos secundarios graves fueron se dieron con menor frecuencia en los grupos que tomaron lersivirina, un 6 y un 14 por ciento en los grupos que tomaron dosis de 500 y 750 mg, respectivamente, en comparación con un 22 por ciento en el grupo que tomó Sustiva.

En total, tres participantes de cada grupo que tomaba lersivirina y cinco participantes del grupo que tomaba Sustiva tuvieron que dejar de tomar los fármacos debido a la gravedad de los efectos secundarios que sufrieron.

Está previsto que el estudio continúe duranre 48 semanas más.

Para obtener más información, consulte la presentación del estudio o el resumen en la página web de la conferencia IAS 2011 (ambos en inglés).

“El dolutegravir administrado una vez al día… mostró una respuesta rápida y sostenida en todas las dosis exploradas hasta la semana 48”, dijo el Dr. Jan van Lunzen, que presentó estos resultados en la 6ª Conferencia Internacional de la Sociedad del SIDA sobre Patogénesis, Tratamiento y Prevención del VIH (IAS 2011).

“El medicamento se toleró bien en todos los grupos de dosis, con menos interrupciones [del tratamiento] que en el grupo de comparación [con Sustiva]”, agregó.

Basándose en los resultados, el Dr. van Lunzen señaló que las Fases 3 de varios estudios clínicos se han iniciado con la dosis de prueba más alta de dolutegravir.

El dolutegravir (S/GSK1349572) es un posible inhibidor de la integrasa nuevo que ViiV Healthcare (una empresa conjunta de GlaxoSmithKline y Pfizer) está desarrollando. En la actualidad, el único inhibidor de la integrasa aprobado es el Isentress (raltegravir), comercializado por la compañía farmacéutica estadounidense Merck.

El estudio clínico se diseñó para probar la seguridad y eficacia de varias dosis de dolutegravir en comparación con Sustiva (efavirenz), que, en combinación con Truvada (emtricitabina/tenofovir) en forma de Atripla (efavirenz/emtricitabina/tenofovir), constituye el tratamiento de primera línea contra el VIH que se prescribe más a menudo.

El estudio incluye a 205 participantes, asignados aleatoriamente a uno de cuatro grupos. El primer grupo recibe 10 mg de dolutegravir una vez al día, el segundo toma 25 mg de dolutegravir una vez al día, el tercero recibe 50 mg de dolutegravir una vez al día, y el cuarto toma Sustiva. Todos los grupos toman sus respectivos medicamentos en combinación con Truvada o Epzicom (abacavir/lamivudina).

Los resultados muestran que, transcurridas 48 semanas, la mayoría de los participantes en los cuatro grupos consiguen alcanzar una carga viral (cantidad de VIH en sangre) indetectable: el 91 por ciento, 88 por ciento, 90 por ciento y 82 por ciento de los participantes en los grupos 1-4, respectivamente.

Los resultados transcurridas 16 semanas, presentados en una conferencia anterior, sugerían que los participantes que tomaban dolutegravir lograban alcanzar una carga viral indetectable más rápido que los participantes que tomaban Sustiva. Los resultados transcurridas 48 semanas demuestran que esa respuesta más rápida al tratamiento con dolutegravir se mantiene durante toda la duración del estudio.

Los participantes que tomaban dolutegravir experimentaron un aumento ligeramente superior en la cantidad de células CD4 (células blancas de la sangre) transcurridas 48 semanas que los participantes que tomaban Sustiva (231 células por microlitro frente a 174 células por microlitro), pero la diferencia no es lo suficientemente grande como para considerarse significativa.

Se informó de menos efectos secundarios moderados o severos en los grupos del estudio que tomaban dolutegravir comparados con el grupo de Sustiva (un 8 por ciento frente a un 20 por ciento de los participantes). Los participantes que tomaron dolutegravir también experimentaron un incremento menor en los niveles de colesterol “malo” durante el curso del estudio que los participantes que tomaron Sustiva, y sus niveles de colesterol total permanecieron estables o aumentaron muy poco.
En total, dos de los participantes dejaron de tomar dolutegravir y cuatro dejaron de tomar Sustiva debido a sus efectos secundarios.

El estudio continuará durante 48 semanas más.

Hay dos estudios clínicos en fase 3 del dolutegravir que necesitan participantes. El primer estudio pondrá a prueba la seguridad y eficacia del dolutegravir comparado con el Isentress en pacientes que han recibido tratamiento previo con regimenes que no incluían inhibidores de la integrasa. El segundo estudio probará la eficacia del dolutegravir en personas que no han respondido al tratamiento con Isentress.

Hay otros dos estudios en de fase 3 en curso que actualmente no necesitan más participantes.

Para obtener más información, consulte la presentación del estudio o su resumen en la página web de la conferencia IAS 2011.

Sustiva (efavirenz), which is in the same antiretroviral class as Edurant (rilpivirine) and an ingredient in Atripla (efavirenz/emtricitabine/tenofovir), is still considered the preferred treatment.

Edurant is a non-nucleoside reverse transcriptase inhibitor (NNRTI) marketed by Tibotec Pharmaceuticals, a subsidiary of Johnson & Johnson. Edurant was approved by the U.S. Food and Drug Administration (FDA) in May.

In addition, Edurant is a component of the once-daily combination pill Complera (rilpivirine/emtricitabine/tenofovir), which was approved by the FDA last week. Complera, which is marketed by Gilead Sciences, is intended as an alternative to Atripla, which is currently the most commonly prescribed first-line regimen for HIV.

Edurant and Complera were approved based on clinical trials showing that they are as effective as Sustiva and Atripla in people who have not previously been treated for HIV. However, the FDA noted at the time that the drugs were not as effective in people starting treatment with viral loads (amount of HIV in the blood) higher than 100,000 copies per milliliter.

In addition, patients taking Edurant or Complera who failed therapy were more likely to show drug resistance than patients taking Sustiva or Atripla.

As a result, HHS has decided to list Edurant as an alternative NNRTI for people starting treatment for the first time, while keeping Sustiva as the preferred NNRTI. The recommendation also affects Complera, which contains Edurant.

HHS defines an alternative regimen as one that is safe and effective but may have disadvantages compared to preferred regimens. Alternative antiretrovirals may be preferred for some individuals due to side effects, allergic reactions, drug resistance, or other factors.

HHS also noted that there is insufficient information on the safety and efficacy of Edurant and Complera in pregnant HIV-positive women. Edurant and Complera are not recommended for children under 18 because appropriate dosages have not yet been determined for this age group.

In addition, HHS warned against use of Edurant and Complera in combination with stomach acid reducers.  Specifically, the antiretrovirals should not be used with proton pump inhibitors, such as omeprazole (Prilosec) and Nexium (esomeprazole), and should be used with caution with antacids and H₂ receptor antagonists, such as cimetidine (Tagamet) or famotidine (Pepcid).

For more information, please see the AIDSinfo website.

In addition, participants taking Isentress (raltegravir) reported fewer side effects than those taking Sustiva (efavirenz).

“In this Phase 2 study, Isentress demonstrated comparable efficacy and tolerability to efavirenz [Sustiva] at 240 weeks in treatment-naïve adult patients with HIV-1,” said primary investigator Dr. Eduardo Gotuzzo in a press release. Dr. Gotuzzo presented the results last week at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

He also noted that the effects of Isentress on cholesterol levels were minimal over the course of the study.

“Because physicians consider many factors when selecting antiretroviral therapy for adult HIV-1 patients new to treatment, the results seen in this Phase 2 study with Isentress in combination therapy showing a modest impact on LDL [“bad” cholesterol] and triglycerides provide important insights,” said Dr. Gotuzzo.

The antiretroviral Isentress is currently the only approved integrase inhibitor, although two other investigational integrase inhibitors – dolutegravir and elvitegravir – are currently in Phase 3 clinical trials.

Isentress is approved both for treatment-experienced adults with HIV and as a first-line treatment for people who have not previously taken antiretrovirals.

In this study, researchers compared the safety and efficacy of Isentress to those of Sustiva over an extended period to see how Isentress performed long-term.

Sustiva, in combination with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen for people with HIV.

Both Sustiva and Isentress, when taken with Truvada, are listed in HIV treatment guidelines as “preferred” regimens for people starting antiretroviral therapy for the first time.

The study included 198 treatment-naïve HIV-positive adults. Participants were initially randomly assigned to take either Sustiva or one of four different Isentress dosages, both in combination with Truvada. After 48 weeks, all 160 participants taking Isentress were moved to the 400 mg twice daily dosage; the remaining 38 participants continued to take Sustiva once daily. The trial lasted 240 weeks.

Results showed that at the end of the study, 69 percent of participants taking Isentress had successfully achieved and maintained an undetectable viral load (amount of HIV in the blood), compared to 63 percent of participants taking Sustiva.

In addition, participants taking Isentress had an average increase in CD4 (white blood cell) count of 302 cells per microliter over this period, versus an average increase of 276 cells per microliter in participants taking Sustiva.

The differences between the two study groups were not large enough to be considered significant.

Fewer patients taking Isentress reported side effects (55 percent) than those taking Sustiva (76 percent). Consistent with other clinical trials, participants taking Sustiva were more likely to report neuropsychiatric symptoms such as dizziness, headache, abnormal dreams, insomnia, and nightmares.

Participants in both groups experienced increases in cholesterol and triglycerides; however, the changes in the Sustiva group were larger than those in the Isentress group, particularly for overall cholesterol levels.

Other side effects, such as nausea and diarrhea, were similar between the two groups.

For more information, please see the study abstract or presentation (pptx) at the IAS 2011 conference website, or the Merck press release.

“Dolutegravir administered once daily…showed a rapid and sustained response at all doses explored through week 48,” said Dr. Jan van Lunzen, who presented the results yesterday at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“The drug in all dose groups was well tolerated, with fewer discontinuations occurring than in the [Sustiva] comparator arm,” he added.

Based on the results, Dr. van Lunzen stated that several Phase 3 clinical trials have been initiated with the highest dolutegravir dosage tested.

Dolutegravir (S/GSK1349572) is a potential new integrase inhibitor being developed by ViiV Healthcare (a joint venture by GlaxoSmithKline and Pfizer). Currently, the only approved integrase inhibitor is Isentress (raltegravir), which is marketed by U.S. pharmaceutical company Merck.

The clinical trial was designed to test the safety and efficacy of several dolutegravir dosages relative to Sustiva (efavirenz), which, when combined with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen to treat HIV.

The study includes 205 participants, who were randomly assigned to one of four groups. The first group is being treated with 10 mg of dolutegravir once daily, the second takes 25 mg of dolutegravir once daily, the third receives 50 mg of dolutegravir once daily, and the fourth takes Sustiva. All groups take the drugs in combination with either Truvada or Epzicom (abacavir/lamivudine).

Results showed that after 48 weeks, most participants in all four groups had successfully achieved an undetectable viral load (amount of HIV in the blood): 91 percent, 88 percent, 90 percent, and 82 percent of the participants, respectively.

Sixteen week results presented at a previous conference suggested that participants taking dolutegravir achieved an undetectable viral load faster than participants taking Sustiva. The 48 week results showed that the more rapid response to dolutegravir was sustained throughout the study period.

Participants taking dolutegravir had slightly higher increases in CD4 (white blood cell) counts after 48 weeks than participants taking Sustiva (231 cells per microliter versus 174 cells per microliter), but the difference was not large enough to be considered significant.

There were fewer moderate to severe side effects reported in the dolutegravir trial groups than in the Sustiva group (8 percent of participants versus 20 percent). Participants taking dolutegravir also had smaller increases in “bad” cholesterol levels during the course of the trial than participants taking Sustiva, with little or no increase in cholesterol levels overall.

In total, two participants stopped taking dolutegravir and four stopped taking Sustiva due to side effects.

The trial will continue for an additional 48 weeks.

Two Phase 3 clinical trials for dolutegravir are currently recruiting participants. The first trial will test the safety and efficacy of dolutegravir versus Isentress in treatment experienced patients who have not previously been treated with integrase inhibitors. The second trial will test the efficacy of dolutegravir in people who have failed therapy with Isentress.

Two other Phase 3 trials are ongoing but are not currently recruiting participants.

For more information, please see the study presentation or abstract on the IAS 2011 conference website.

“Lersivirine is a next generation non-nucleoside reverse transcriptase inhibitor…[that] has potent activity against HIV,” said Dr. Anton Pozniak, who presented the results today at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“Both lersivirine doses [tested] achieved similar viral load suppression to [Sustiva],” he added.

Dr. Pozniak suggested that lersivirine may also be an option for people who are resistant to Sustiva (efavirenz), since the two drugs work slightly differently. However, he noted that the results will need to be confirmed in a larger Phase 3 clinical trial.

Lersivirine (UK-453061) is a potential new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed by ViiV Healthcare, a joint venture of the pharmaceutical companies Pfizer and GlaxoSmithKline.

The Phase 2b clinical trial is designed to test the safety and efficacy of lersivirine versus those of Sustiva, which is also an NNRTI. Both antiretrovirals are taken in combination with Truvada (emtricitabine/tenofovir); Sustiva plus Truvada is equivalent to Atripla (efavirenz/emtricitabine/tenofovir), the most frequently prescribed first-line regimen for people with HIV in the United States.

The trial includes 193 HIV-positive participants who had not been treated with antiretrovirals prior to starting the study. Participants were randomly assigned to receive either 500 mg lersivirine once daily plus Truvada (65 participants), 750 mg lersivirine once daily plus Truvada (65 participants), or Sustiva plus Truvada (63 participants).

Results showed that after 48 weeks, 79 percent of participants taking lersivirine had achieved an undetectable viral load (amount of HIV in the blood) compared to 86 percent of participants taking Sustiva. The difference in efficacy between the two drugs was not large enough to be considered significant.

Increases in CD4 (white blood cell) counts were similar across the three groups, at 191, 195, and 188 cells per microliter for the 500 mg lersivirine, 750 mg lersivirine, and Sustiva groups, respectively.

The reported side effects for lersivirine were different than those for Sustiva. The most common side effects in the lersivirine groups were nausea (23 percent and 42 percent for the 500 mg and 750 mg groups, respectively) and headache (23 percent and 17 percent for the 500 mg and 750 mg groups, respectively). The most common side effects in the Sustiva group were abnormal dreams (19 percent) and dizziness (21 percent).

Severe side effects were less common in the lersivirine groups, at 6 percent and 14 percent for the 500 mg and 750 mg dosage groups respectively, compared to 22 percent in the Sustiva group.

Overall, three participants from each lersivirine group and five participants in the Sustiva group discontinued the drugs due to side effects.

The trial is scheduled to continue for an additional 48 weeks.

For more information, please see the study presentation or abstract at the IAS 2011 conference website.

The authors noted that their results provide further justification for listing Truvada as a preferred combination regimen and Combivir and Epzicom as alternative regimens.

However, the study appears to be based on the separate costs of Truvada and Sustiva pills rather than Atripla, the once-daily pill that combines Truvada and Sustiva. The study also did not take into account the possibility of generic Combivir, which was approved by the U.S. Food and Drug Administration last month (see related AIDS Beacon news) and is expected to be available later this year.

The study authors also pointed out that some studies have suggested that Truvada may not be as effective for people who start treatment at lower viral loads, in which case Truvada may not be as cost-effective for these patients.

According to the study authors, rising drug costs and longer life expectancies for people with HIV mean that the costs of antiretroviral therapy have now become an important consideration.

In addition to the direct cost of the drugs, total health care costs are affected by the efficacy of a person’s first-line therapy and his or her long-term health. Low viral loads (amount of HIV in the blood) and high CD4 (white blood cell) counts, which are achieved with treatment, prevent disease progression and other illnesses associated with HIV.

First-line therapies are also more likely to have easier dosage schedules and are usually less expensive than later antiretroviral regimens. As a result, the longer a person can stay on first-line therapy, the lower his or her long-term health costs are expected to be.

Currently, U.S. treatment guidelines for HIV recommend that first-line therapy consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus at least one drug from another antiretroviral class. Truvada (emtricitabine/tenofovir), a combination of two NRTIs, is listed as the preferred combination of NRTIs, and the non-nucleoside reverse transcriptase inhibitor Sustiva (efavirenz) is listed among the preferred drugs to use in combination with NRTIs..

The two-NRTI combination pills Combivir (lamivudine/zidovudine) and Epzicom (abacavir/lamivudine) are listed as alternatives to Truvada.

In this study, the authors compared the cost-effectiveness of Truvada, Combivir, and Epzicom, each used with Sustiva, as first-line treatments in HIV-positive adults.

The authors developed a computer model for each first-line therapy that included annual drug costs, drug efficacy, medical costs related to treatment of side effects and HIV-related illnesses, the cost of switching antiretroviral regimens when a first-line regimen is no longer effective, and the estimated costs of second- and third-line treatment regimens based on current treatment guidelines.

Information such as drug efficacy, side effects, and failure rates were obtained from a 144-week study of Sustiva plus Truvada or Combivir and a 48 week study of Sustiva plus Combivir or Epzicom.

Results showed that Truvada was the most cost-effective NRTI combination for a first-line treatment regimen, with patients predicted to remain on the drug for almost eight years. Estimated lifetime costs for HIV treatment for people starting with Truvada plus Sustiva were $747,327.

Patients taking Epzicom were predicted to remain on the therapy for six years and accrue lifetime costs for HIV treatment of $777,090, and patients on Combivir were predicted to remain on it for almost six years with lifetime costs of $778,287.

The lower overall cost for Truvada was primarily a result of its greater efficacy, which delayed disease progression and allowed patients to remain on treatment longer.

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

“Our study suggests that more sensitive genotypic HIV drug resistance assays, such as deep HIV sequencing, may help clinicians design antiretroviral treatment combinations better suited for [patients] infected with multidrug-resistant viruses,” said Dr. Roger Paredes, a key investigator of the study, in correspondence with The AIDS Beacon.

“Deep sequencing may help [clinicians] choose more effective drugs as well as avoid antiretrovirals to which, in fact, the virus is resistant,” he added.

Drug resistance is one of the main causes of antiretroviral drug failure. HIV-positive individuals are considered resistant to an anti-HIV drug if their viral load (amount of HIV in the blood) does not remain low after drug therapy or testing confirms the presence of an HIV strain that is resistant to one or more classes of antiretrovirals.

Resistance testing examines the genes of the HIV in a person’s blood to detect whether the virus has mutations that make it resistant to particular drugs. Previous studies have indicated that even low levels of drug-resistant HIV increase the chances of treatment failure, although those studies have primarily involved previously untreated people with HIV (see related AIDS Beacon news)

The authors of this study investigated whether an enhanced form of resistance testing, known as deep sequencing, could provide better assessments of drug resistance in heavily pre-treated HIV patients when compared to the more traditional form of resistance testing, called population sequencing.

Deep sequencing detects the same mutations as population sequencing but is more sensitive, so it can detect mutations present in 1 percent or more of the HIV circulating in a person’s blood. Population sequencing can usually only detect mutations present in 15 percent or more of the HIV.

Seven HIV-positive individuals participated in the study. Participants had taken a median of 15 antiretroviral drugs for a median of 13 years. The average age of the participants was 44, and five of the seven were male.

All participants had shown resistance to the three main classes of antiretrovirals: nucleoside-reverse transcriptase inhibitors (NRTIs), protease inhibitors, and non-nucleoside reverse transcriptase inhibitors. In addition, all participants had failed salvage therapy with at least one of the following: Prezista (darunavir), Aptivus (tipranavir), Intelence (etravirine), or Isentress (raltegravir).

Results showed that deep sequencing detected all of the drug resistant mutations found by population sequencing, plus additional resistance mutations in six of the seven participants.

In particular, deep sequencing improved the assessment of resistance to Intelence, showing higher risk of resistance in two patients with signs of failing Intelence-based therapy. The technique also slightly modified assessments of HIV resistance against Sustiva (efavirenz), Crixivan (indinavir), and NRTIs in various participants to indicate higher risks of resistance, compared to the population sequencing.

The two methods identified the same participants as having drug resistance to Aptivus and Isentress, and the deep sequencing confirmed that four of five participants who had failed Isentress-based antiretroviral therapy did not show resistance to the drug and could potentially take it again.

Dr. Paredes stated that the researchers are currently conducting a larger study to investigate whether the use of deep sequencing can lead to improved treatment outcomes for treatment-experienced patients starting salvage therapy with Norvir (ritonavir)-boosted protease inhibitors, Intelence, or Isentress.

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