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August 31, 2010 Visit the Forums “Hot Topics” Library Change/Update Subscription



LIVING WITH HIV/AIDS
 Recently Diagnosed and Extremely Anxious: How Can I Cope?
I’m a heterosexual jock with a gorgeous girlfriend, and I recently tested HIV positive. I’ve been feeling horrible ever since. I thought my girlfriend would dump me when I told her, but she’s been amazing. She’s tested negative so far, and we’ve decided not to tell anyone about my diagnosis. Today I was home alone in my bedroom and my heart started racing, I got sweaty and couldn’t breathe or move. I might have even blacked out for a bit. It was the most terrifying feeling of my life. What’s happening to me?

 Dear Dr. McGowan: When Was Your 88-Year-Old Patient Diagnosed With HIV?
In a recent forum response you mentioned you see an 88-year-old HIVer in your medical practice. How long has that person been HIV positive? If she or he has had the virus since the 1980s and lived to be 88, knowing that would be an inspiration for your readers.
BEYOND HIV/AIDS MEDICATIONS
 Which Supplements Will Provide the Most “Bang” for the Fewest Bucks?
I’m on a limited income and don’t have a lot of extra money to spend on vitamins, which aren’t covered by insurance. If I had to pick just a few supplements to take that would be affordable and provide the most benefit, what would you recommend?


 HIV, Hepatitis B, Atripla and P90X Post-Workout Drink: Any Problems?
Is it safe to use P90X Results and Recovery Formula while taking Atripla (efavirenz/tenofovir/FTC)? I consume two scoops of the nutrient-rich drink with water once daily after working out. Could this formula cause Atripla drug levels to decrease — or affect my undetectable hepatitis B viral load?
"This Positive Life" Video Series

Far too many people with HIV live in isolation, dealing with their diagnoses, medical visits, meds, health issues and stigma all by themselves.

Each month, TheBody.com’s This Positive Life video series will bring you two new interviews to watch (or read!). These inspiring videos feature HIVers from all walks of life as they talk about what it means to live — and live well — with HIV.


HIV/AIDS TREATMENT
 Can I Take a Yearlong Break From HIV Meds?
I’ve been HIV positive for four years and on HIV meds for three and a half years. I’m 50 years old, my viral load is undetectable and my CD4 count is 550. I eat well, exercise and feel great, health-wise, but recent changes in my career have been mentally exhausting. I’d love to take a year off to travel, but I keep working in fear of losing my insurance. Can’t I just take a year off from HIV meds so I won’t need insurance?

 High Viral Load and Low CD4 Count in Acute Infection: Should I Start Meds?
I had an HIV-negative test result on June 28 and had been tested consistently for years beforehand. I got sick in July and was diagnosed HIV positive at the end of the month with a CD4 count of 158 and a viral load of 3 million. My counts have improved somewhat since then, but my doctor wants me to start HIV meds. I didn’t expect to need meds so soon. Won’t my CD4 count go up further on its own?

 When Should an HIV-Positive Woman Start Meds When Planning a Pregnancy?
I know a 35-year-old HIV-positive woman with a CD4 count of 820 and a viral load of 1,897. She’s not on HIV meds but her husband, who’s also positive, has been taking meds for eight months. When should this woman start taking meds if she’s planning to get pregnant, and how should she choose her regimen?

More Questions About HIV/AIDS Treatment:

OTHER HEALTH ISSUES & HIV/AIDS
 Will My HIV Med Switch Ever Have an Effect on My Neuropathy?
I took Epivir (lamivudine, 3TC), Sustiva (efavirenz, Stocrin) and Zerit (stavudine, d4T) for a year, but I developed peripheral neuropathy so I switched out the Epivir and Zerit for Truvada (tenofovir/FTC). It’s been two months now and the neuropathy isn’t getting better and the pain is sometimes unbearable. Is there anything else I can do?

 Are Platelet-Rich Plasma Injections Safe for HIVers With Orthopedic Injuries?
There’s a procedure called platelet-rich plasma injection that’s becoming common in orthopedic procedures, in which a sample of a person’s blood is drawn and spun down to concentrate the platelets. These are then re-injected into the wounded area, the thinking being that the oxygen-rich platelets help speed healing. Would there be an issue doing this procedure on an HIV-positive person?
Connect With Others Taking Meds — and Hating the Daily Reminder That I Have HIV
(A recent post from the "Treatment" board)

I started HIV meds two weeks ago because my viral load was 100,000 and my CD4 count dropped to below 500. I don’t have any physical issues with meds — it’s more emotional. It’s a twice-daily reminder of HIV, and before I could forget about it for a while. Has anyone else ever felt this way about taking meds? — frank74

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UNDERSTANDING HIV/AIDS LABS & TESTING
 Why Isn’t My Viral Load Undetectable After 8 Weeks on HIV Meds?
I was diagnosed in early HIV infection in April and started taking Isentress (raltegravir) and Truvada (tenofovir/FTC) in June. My viral load when I started meds was 690,000 and my CD4 count was 154. Four weeks later my viral load was 296 and my CD4 count was 300. At the eight-week mark my viral load was 128 and my CD4 count was 278. Since I made such good progress after four weeks, shouldn’t my viral load be undetectable by now?

 What’s the Deal With False-Negative HIV Tests?
What is the likelihood of someone receiving a false-negative HIV test result? What could cause a test to be a false negative?

More Questions About Understanding HIV/AIDS Labs & Testing:

STRANGE BUT TRUE
 Could a Neighborly Mosquito Deliver a Shot of HIV to My Eye?
Are there any flying insects that can transmit HIV right after they bite an HIVer? A bug flew into my eye recently. If the bug had come directly from biting my neighbor, who’s HIV positive, could I be infected?

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 Action Alert: Say NO to Abstinence-Only Sex Education

 President Obama: Address the ADAP Crisis!

 NMAC Asks for Your Help Ending S.B. 1070; Promoting Comprehensive Federal Immigration Reform

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Doctors Seek Way to Treat Muscle Loss

Nandrolone can do this easily, as long as doctors have a very close monitoring on hematocrit since older men tend to have more problems with polycythemia

Can HIV medications treat Chronic Fatigue Syndrome?

A study published in the Public Library of Science (PLoS) in 2010 concluded that four anti-HIV drugs also inhibit XMRV replication.[33] The drugs were two retroviral integrase inhibitors; raltegravir (Merck & Co., brand name Isentress), L-000870812 (Merck & Co.), and two nucleoside reverse transcriptase inhibitors; tenofovir disoproxil fumarate (Gilead Sciences, brand name Viread), and zidovudine (GlaxoSmithKline, azidothymidine (AZT)). Synergistic effects were reported when the drugs were used in combination.

Spanish Information about my new book- Informacion es Espanol sobre mi nuevo libro sobre la testosterona

Introducción
Mi relación con la sustitución hormonal ha sido larga y fructífera. Yo fui diagnosticado con testosterona baja en 1993, a la edad de 34, luego de haber estado viviendo con VIH por 11 años. Yo había perdido 14 libras (6,35 Kg) involuntariamente, me sentía cansado y deprimido, y no tenía deseo sexual en lo absoluto. Estaba convencido que ese sería el comienzo del fin para mi. Muchos de mis amigos con VIH comenzaron a verse como esqueletos debido al síndrome de desgaste, una pérdida de peso corporal severa e involuntaria. Y luego varios murieron. Yo comenzaba a creer el mito de que sentirse cansado y terminar siendo huesos era normal si uno es VIH positivo.
Afortunadamente, en Los Angeles conocí hombres VIH positivos en grupos de apoyo, quienes ya estaban usando testosterona de manera clandestina. Ellos presumían sobre lo grandioso que se sentían y se veían. Para ese entonces, yo estaba aterrorizado de considerar la hormona, ya que había escuchado que ésta causaba cáncer prostático y hepático, destruía el sistema inmunológico, y supuestamente inducía una “furia esteroide” horrible. Finalmente me convencí de tomar un riesgo controlado cuando mi miedo a morir por desgaste se tornó más fuerte que mi miedo a los esteroides.
Pude conseguir un poco de cipionato de testosterona e hice que un amigo me ayudara a inyectar 200 mg en la parte superior de mi nalga. Después de dos inyecciones (con una semana de intervalo), comencé a mejorar: Mi mente estaba menos nublada, mi apetito sexual estaba regresando, mi depresión disminuyó y mi pérdida de peso se estabilizó. Me sentí como si estuviese vivo de nuevo y recobré mi apetito, no sólo por la comida, sino por la vida en sí. Lo que yo pensaba que eran síntomas de deficiencia inmunológica, eran síntomas de tener testosterona baja. Comencé a sentirme como debería sentirse un hombre saludable de 34 años. Con la ayuda del ejercicio y la nutrición adecuada, pude aumentar 35 libras (15,88 Kg) de masa corporal magra, aún con el virus del VIH no controlado en mi sangre. Tuve esperanza otra vez.
Mi increíble transformación me inspiró a leer todo lo que pude sobre la testosterona y los andrógenos en publicaciones médicas. Esto inició una travesía que me ha llevado a través de 16 años de autoeducación en la materia. En 1999 coescribí un libro llamado “Hecho Para Sobrevivir: Una Guía Integral para el Uso Médico de Hormonas Anabólicas”, con Michael Mooney, sobre los usos médicos de andrógenos, ejercicio y nutrición para contrarrestar el desgaste relacionado al VIH y mejorar la calidad de vida. Después del lanzamiento de ese libro, recibí muchos correos electrónicos de hombres saludables VIH negativos con preguntas sobre la testosterona. Me di cuenta que la información recolectada por nosotros sobre el VIH era invalorable también para hombres sin el virus. Así que decidí escribir este libro para todos los hombres que necesiten ayuda, independientemente de su estado de salud.
Desde su descubrimiento a principios del siglo XX, el mundo ha aprendido mucho sobre la testosterona. Desafortunadamente, la testosterona es, también, quizás una de las hormonas menos comprendidas en la medicina. El estigma, el rechazo y la errada definición han sido barreras para que la mayoría de los hombres consideren su uso – aún con la presencia de todos los síntomas debilitantes de la deficiencia de testosterona (hipogonadismo). Estos miedos han sido exacerbados por unos medios de comunicación que equiparan el suplemento de testosterona con la agresión y con los atletas que abusan de él, así como también por los médicos que tienen poca comprensión acerca de la terapia de reemplazo de testosterona (TRT).
Los resultados de uno de los estudios más grandes que se han realizado en deficiencia de testosterona, el estudio de Hipogonadismo en Hombres (HIM, por sus siglas en inglés), publicado en el 2006, estimó la prevalencia general de hipogonadismo en los Estados Unidos en aproximadamente 39 por ciento en los hombres de 45 años o más. Estimaciones recientes muestran que 13 millones de hombres en los Estados Unidos pueden experimentar deficiencia de testosterona, sin embargo menos del 10 por ciento recibe tratamiento para esta condición. Entonces ¿Por qué tantos hombres están recibiendo tratamiento para hipogonadismo?
Tenga en cuenta que los hombres se caracterizan por no visitar a los doctores proactivamente. Y considere también que los dos síntomas principales de deficiencia de testosterona, la depresión y la disfunción sexual, son temas que hacen sentir incómodos a la mayoría de los hombres, inclusive al discutirlos con sus médicos. Así que, aunque él se sienta lo suficientemente mal como para acudir finalmente al doctor, un hombre probablemente está más dispuesto a recibir un golpe físico en el estómago, que uno en sentido figurado, al admitir abiertamente que tiene problemas con su desempeño sexual o su estado de ánimo.
Muchos hombres sufren, sin necesidad, estos problemas que afectan dramáticamente su calidad de vida y su relación con otros. Tanto la depresión como la disfunción sexual han sido relacionadas con factores de riesgo cardiovascular que afectan no sólo el tiempo de vida, sino lo más importante, la calidad de ésta. Envejecer y mantenerse saludable e independiente es, con seguridad, el deseo de todos. Este libro le proporcionará una de las piezas del rompecabezas sobre cómo alcanzar esta meta.
Desde mi último libro, muchos estudios han demostrado que la testosterona es una hormona importante y relativamente segura para aquellos con deficiencia de testosterona que son monitoreados por un médico capacitado. Los nuevos productos, como los geles de testosterona, han penetrado el mercado y han ayudado a aumentar, entre los médicos, el conocimiento sobre la testosterona. Pero la satanización de esta hormona y de sus moléculas primas, los esteroides anabólicos, no ha desaparecido, mayormente debido a miedos infundados por la falta de información. Lamentablemente, los medios de comunicación y el Congreso de los Estados Unidos se han enfocado en la testosterona empleada por los atletas que utilizan estos compuestos en dosis altas sin consultar a médicos capacitados. Esta histeria de los medios de comunicación quizás se sume al miedo a los efectos secundarios de la testosterona, presente en las mentes de los pacientes potenciales que viven con hipogonadismo, quienes están sufriendo sin necesidad y en silencio.
Además de obtener información de diferentes opiniones, he probado, deliberadamente, la mayoría de los productos que menciono en este libro para brindar datos prácticos de cada uno de ellos. En los últimos 16 años, también he tenido la fortuna de aprender, vía Listserv en-línea y conferencias, de experiencias de muchas personas que utilizan estos productos. Es mi esperanza que este libro ahorre tiempo y trabajo a los lectores, evitando errores costosos, tiempo perdido y sufrimiento innecesario. Traté de escribirlo en un lenguaje accesible. Mis sugerencias no tienen la intención de ser consejos médicos, y le ruego firmemente a cada lector buscar la opinión de un doctor calificado y capacitado, antes de iniciar cualquiera de las soluciones de salud reseñadas en este libro.
También he incluido información útil sobre programas de asistencia al paciente y cómo conseguir médicos capacitados en la terapia de reemplazo de testosterona para ahorrar dinero y tiempo valioso para los hombres en búsqueda de soluciones a su hipogonadismo.
A pesar que este libro se enfoca en hombres, usted notará que he incluido alguna información sobre la testosterona en mujeres. Hasta el 2010, no existen productos de testosterona para mujeres aprobados por la Administración de Alimentos y Fármacos (FDA, por sus siglas en inglés), sin embargo, algunos doctores han estado recetando dosis pequeñas en cremas compuestas especialmente para la ausencia de libido en mujeres. Existen, inclusive, algunos productos en estudio y próximos a potencial aprobación para mujeres.
Por favor no dude en escribirme vía mi página web TestosteroneWisdom.com, una página creada para proporcionar información actualizada tan pronto como se encuentre disponible. Asimismo, por favor hágame saber lo que piensa, publicando su opinión en amazon.com.
Deseándole excelente salud y prosperidad.
Nelson Vergel.

New Drugs and New Combinations – How will They Change What We Do?

IAC Summary on New Drugs and New Combinations – How will They Change What We Do?
 Vienna July 18-23 2010
Joe Eron, Univ of North Carolina
This year’s IAC was one of the most exciting and data-filled International AIDS meetings since Vancouver in 1996.  The defining presentation of the meeting was the CAPRISA 004 study that demonstrated that a topical microbicide (tenofovir gel) prevented HIV infection in at-risk women in South Africa.  The excitement in the room during the series of presentations was palpable and the presentations were interrupted several times by applause.  Much as Vancouver signaled the beginning of the HAART era, perhaps CAPRISA 004 will signal the practical beginning of the Antiretroviral Prevention era.  Certainly a prevention intervention that can be controlled by at-risk women is a true breakthrough. The hallway discussions were about the magnitude of the effect (Did we expect more? Did we expect less?), the obvious importance of adherence and perhaps the challenging questions about whether a second confirmatory study was needed before this intervention could be made available to women and whether placebo arms should still be incorporated in further studies of microbicides and other pre-exposure prophylaxis (PrEP) studies in women. 
While CAPRISA 004 was a clear centerpiece of the meeting there were also several presentations of antiretroviral therapies (used as treatment in the old fashioned way) that were quite important and will certainly impact how we treat our patients over the next 2-3 years.
ECHO and THRIVE
The most important of these presentations was made by Cal Cohen who presented the Phase III data comparing rilpivirine head-to-head with efavirenz when both were combined with two NRTI (predominantly tenofovir DF/FTC fixed dose combination) in treatment naïve patients. These data are the most clinically relevant because this was one of only two presentations of phase III data in treatment naive patients, because it looks like rilpivirine is ready to be combined with TDF/FTC in a fixed dose combination and most importantly, because Tibotec has submitted the new drug application (NDA) for this drug on July 28th 2010. The full details of Dr. Cohen presentation can be found in the detailed NATAP summary but there are several interesting nuances to the results that we will probably be discussing and debating for some time.  First and foremost in the primary analyses of both studies, which were independent well powered studies (EHCO used FDC TDF/FTC as the NRTI backbone in all patients, whereas THRIVE allowed the use of TDF/FTC, ZDV/3TC or ABC/3TC as the backbone though the majority of the participants received TDF/FTC), rilpivirine with 2 NRTI was non-inferior to EFV and 2 NRTI in intention-to-treat analyzes (VL <50 c/mL, ITT-TLOVR at Week 48).  Both arms in each study performed very well in a challenging population (median baseline viral load was 100,000 c/mL). In the analysis that combined the results of the 2 studies 84.3% of participants on RPV-based therapy had HIV RNA < 50 copies/mL at 48 weeks compared to 82.3% of participants on the EFV-based therapy.  The “non-inferiority” of RPV was well established with the lower bound of the confidence interval at -2.2%, way below the non-inferiority bound of -12%. Though I am sure this is not FDA-kosher you could almost call the two therapies (when viewed in the light of the combined results) “equivalent”.  However ….. RPV-based and EFV-based therapy produced such similar overall results for different reasons.

Bioequivalence of the Co-Formulation of Emtricitabine/Rilpivirine/Tenofovir DF – (08/04/10)

RPV-based therapy was clearly better tolerated than EFV-based therapy.  In the results from the 2 studies combined, Grade 2-4 AE that were at least possibly related to study medication were twice as likely on EFV-based therapy (31% vs. 16%, p < 0.0001) and significantly fewer participants receiving RPV-based therapy discontinued study medication compared to those on EFV-based therapy (3% vs. 8% p = 0.0005).  These discontinuations of course are counted as failures in the TLOVR-ITT analysis.  As anticipated neurologic and psychiatric adverse events were significantly and substantially less common with RPV and unanticipated (at least by me) was that rash was also significantly less common (3% vs. 14% p < 0.0001). Grade 3-4 laboratory abnormalities were also significantly less common in RPV-treated participants.  While no single grade 3-4 lab abnormality was very common in either arm, grade 3-4 increases in ALT, LDL cholesterol, total cholesterol and triglycerides were all less common with RPV.  Mean change in all individual lipid parameters (including HDL) were greater with EFV with very little change in any of the parameters in those participants on RPV-based therapy.  Because HDL also rises on EFV-based therapy the total cholesterol to HDL ratios at week 48 were not significantly different between the two treatment groups in the combined analysis.
The flip side to the superior tolerability data for RPV-based therapy was that virologic failures (as defined in the TLOVR analysis) were approximately twice as common in participants on RPV (9.0% vs. 4.8% in the combined analysis, p value not reported but likely very significant). So in effect, the discontinuations due to AE (approximately a 5% difference) are balanced by VF (approximately a 4% difference).  There were some relatively small but curious differences in VF between the two studies with a greater difference in VF in the ECHO study (6.6%), where all participants received TDF/FTC, compared to THRIVE (1.8%), where there was a choice of NRTI.  We were told that response rates were not different in THRIVE by NRTI choice so we don’t really have an explanation for this difference in virologic failures.  Perhaps the participants in THRIVE were more likely to take their medications more consistently (the difference in discontinuations due to AE between the two arms was also somewhat less in THRIVE).
The resistance consequences were also different between the two treatment groups as one might expect. Sixty-two participants out of 686 on RPV had virologic failure with resistance data available compared to 28 out of 682 participants on EFV-based therapy.   In these participants with VF and resistance data, the likelihood of acquiring at least one mutation was greater in RPV recipients (71% vs. 57%) and while the proportion with NNRTI resistance was similar (63% vs. 54%), NRTI mutations were more common in RPV failures (68% vs. 32%). The most frequent NNRTI RAM in VF with resistance assays on the EFV arms was the well known K103N mutation.  However in participants with VF on the RPV arms the most common NNRTI resistance mutation was E138K.  Preliminary phenotypic information demonstrated that virus that developed resistance to RPV were likely to be cross resistant to etravirine. 
These data suggest that there may be a subtle difference in potency between efavirenz and RPV given at the dose chosen for the Phase III studies. Recall that higher doses of RPV (while well tolerated) were associated with QT prolongation on ECG. Therefore doses of 75 mg and 150 mg daily (as opposed to the dose of 25 mg daily that was chosen) were not acceptable for the Phase III studies.  If we examine the results in the sub-groups with viral load < 100,000 and > 100,000 we find support for the potency argument.  In the participants with lower viral loads (VL) RPV-based therapy performed very well as the tolerability advantage held sway. In fact, in the analysis of the combined study RPV-based therapy was actually superior to EFV-based therapy as the potential subtle difference in antiviral activity  was not a disadvantage in the lower viral load group. In higher viral load group the overall result was that RPV was still non-inferior though the proportion responding was numerically less in the RPV-treated participants.  The hypothesis is that the tolerability advantage is somewhat neutralized by more virologic failures.  The differences between the two trials also show up here.  In THRIVE there is little difference in overall response in the high viral load groups between RPV and EFV (79% vs 80% < 50 c/mL at 48 weeks by ITT TLOVR), whereas in ECHO the results were 76% and 82% respectively.  There was no obvious explanation for this difference between studies but one could imagine if there were modest difference in drug exposure (perhaps due to adherence) in the two studies that might explain the results. If RPV is more on the cusp of its concentration to activity ratio then small differences in exposure or very high viral loads might result in a greater risk of virologic failure. In contrast the response rates on efavirenz were very consistent across the two studies and in the lower and higher viral load groups. This result is very consistent with our experience with EFV-based therapy in almost all other studies. For now though my speculation is only one possible hypothesis, which perhaps will be confirmed with more detailed analyses that include drug concentration measurements and further sub-analyses of the two studies.
The results of ECHO and THRIVE and the combined analyses set up an interesting discussion about how we will use EFV/TDF/FTC and RPV/TDF/FTC if RPV (and perhaps the fixed dose combination) is approved in early 2011, which seems very likely. At some point next year we will likely have two “one pill once a day” therapies. There is a clear tolerability advantage to RPV, which is a substantial plus as we move to treating asymptomatic patients with higher and higher CD4 cell counts. On the other hand there will be concerns about the increased risk of virologic failure that may be more likely in patients who have higher baseline viral loads. Again the sequencing argument will be raised.  If you have virologic failure on RPV-based therapy it appears likely that the patient’s virus will also be etravirine resistant, whereas if you have virologic failure on EFV based therapy and the only mutation is K103N then etravirine will still have full activity.  We hate losing a drug, even if we weren’t planning to use it any time soon.  Alternatively the loss of etravirine in a small fraction of patients who start RPV-based treatment will have very little practical consequence as there are multiple antiretroviral combinations available for first line failures.  There will also be discussions of the better lipid effects of RPV, however we don’t have the very long term safety data that we have with EFV.  RPV has NOT shown any teratogenicity in lab based and preclinical studies and will likely be a category C medication.  Many care providers and HIV-infected women of child bearing potential may then prefer RPV based therapy.  Another potential option will be to switch to RPV-based therapy (especially when the combination pill is approved) once patients are suppressed.  Obviously this strategy has not yet been studied but I suspect it will be, once rilpivirine is available.  There also will be a lot more data forth coming from the ECHO and THRIVE studies including new sub-analyses and eventually the 96 week data. While I don’t think ECHO and THRIVE can be considered a “home run” I think we all look forward to having rilpivirine and another one pill once a day therapy available to us soon.
THE “ING” STUDIES
We learned a lot more about another promising drug, the Shionogi GSK integrase inhibitor S/GSK 1349572.  This drug, “572”, was introduced last summer at the IAS meeting in Cape Town and was shown to be very potent in a short term monotherapy study in integrase inhibitor naïve subjects reducing plasma HIV RNA by over 2 log10 over 10 days.  In Vienna we saw longer term phase IIb data in treatment naïve individuals and we saw the initial activity of this drug in raltegravir failures who had documented integrase inhibitor resistance.  
The treatment naïve study, called SPRING, was a partially blinded phase IIb 48 week study examining 3 different doses of 572 (10, 25 and 50 mg) with a comparator arm of efavirenz each combined with 2 NRTI (approx 2/3 TDF/FTC and 1/3 ABC/3TC).  Sixteen week data were shown and demonstrated very rapid suppression (consistent with previous raltegravir and elvitegravir data) in each of the three 572 arms with over 80% of patients suppressed to < 50 c/mL by week 8 and 90% or more < 50 c/mL at week 16 in each of the 3 arms.  Again consistent with raltegravir data the speed of suppression was significantly faster with 572 compared to efavirenz-based though it is likely that over 48 weeks the treatment arms will look similar in the relatively small study of 50 participants per arm.  572 was very well tolerated and there were no serious adverse events related to 572 and very few discontinuation in any of the arms.  The highest dose (50 mg once daily) was chosen for further development though the 3 572 dose arms in this study will be continued through 48 weeks as there are little long term data with this agent. The potential advantages of 572 in naïve patients over other integrase inhibitors include; once daily dosing that does not require a boosting agent, a low mg dose that will allow co-formulation and probable single pill therapy and a predictable concentration activity relationship (pharmaco-dynamic profile).  The drug seems very well tolerated over the short term, like other integrase inhibitors, which is likely to be an advantage even when comparing across class, though clearly longer term tolerability and toxicity data are needed as well as data on lipid changes and other laboratory markers. Based on the SPRING results the naïve treatment market is likely to get more crowded with multiple good choices over the next several years.
I had the good fortune to present the VIKING study, which examined the short term activity of 572 in patients with documented RAL resistance.  The results of this study were interesting and more complex than the very straightforward results of the SPRING study.  In this study participants had to have documented RAL resistance at screening and could either be on RAL-based combination therapy or combination therapy without RAL, having failed RAL in the past with persistent resistance. Based on in vitro susceptibility data there were 2 groups of subjects. One group had integrase resistance mutations at screening at codon 155 with or without others, 143 again with or without other mutations or a single mutation at the 148 codon. The second group had to have a mutation at the 148 codon but then also had one or more secondary mutations. In vitro most viruses with the 155 pattern or the 143 pattern remain fully or nearly fully susceptible to 572. In contrast viruses that have the 148 mutation plus additional mutations (usually 140S with or without others) have decreased susceptibility to 572, though the fold change of some of these viruses are in a range where 572 might still have activity.  All participants received 572 functional monotherapy for 10 days at 50 mg daily. Those who were on RAL (the majority) had RAL replaced by 572 with continued background. Those who had already stopped RAL and were on a stable combination regimen had 572 added for the 10 day period. On day 11 participants were allowed to optimize their background therapy and continue the 572.  Only the functional monotherapy data were presented. 
Twenty-seven subjects were enrolled, 18 in group 1 and 9 in group 2. At baseline the median CD4 cell count was 110 and median viral load was approximately 30,000 c/mL.  These were highly treatment experienced patients. They had received a median of 17 antiretroviral agents in the past and the majority had been exposed to darunavir, enfuvirtide and etravirine.  The median baseline fold change to RAL was 161 while the median baseline fold change to 572 was 1.5.  There was a clear relationship between the pattern of RAL resistance mutations and the baseline fold change with the highest fold changes seen when the codon 148 mutation was present with 2 or more secondary mutations. Viruses with the 143 mutation (with or without other mutations) had minimal if any shift in susceptibility to 572.  The primary endpoint of the study was at least a 0.7 log10decline in HIV RNA from baseline or a viral load < 400 c/mL at day 11.  Response rates were consistent with the in vitro data and the baseline genotype and phenotype data.  All 18 participants in group 1 (virus with 155 or 143 complex mutations) met the primary endpoint with a mean change in HIV RNA of 1.82 log10. Eight out of 18 had HIV RNA < 400 c/mL at day 11 and one was < 50 c/mL.  In contrast only 3 of the 9 subjects in group 2 with 148 plus at least one additional mutation met the primary endpoint, though all 3 did fall to < 400 c/mL. The mean change in this group was 0.72 log10.  Overall there was a very strong inverse correlation between baseline fold change and the change in HIV RNA at day 11.  Importantly no participant had emergence of a new RAL resistance mutation over the 11 day period. In 17/18 subjects in whom baseline and day 11 resistance testing could be accomplished the change in susceptibility was < 2 fold.  A detailed resistance poster was presented by Bonaventura Clotet. He showed that the one subject who had a an approximate 6 fold decrease in susceptibility had a mixture of viruses at baseline and over the 11 day period the virus with the more resistance genotype (148 plus an additional mutation) became the predominant variant and likely accounts for the decrease in susceptibility that occurred over the 11 days of functional monotherapy.
Following the presentation there was a lot of discussion about the results and whether 572 fits the bill as a second generation integrase inhibitor.  Clearly some viruses with substantial resistance to RAL respond very well to 572.  The viruses with the 155 and 143 mutation patterns were not just early failures of RAL. Though the duration of previous RAL therapy for these subjects is known (though not reported in the presentation by Eron et al) the duration of RAL failure for each patient is not known. However, as was shown in the poster by Dr. Clotet, many of the viruses with the 155 and the 143 pathways had multiple mutations and had substantial resistance to RAL.  Participants with these viruses have very good responses over the short term and if adequate partner therapy can be given the response is likely to be durable.  The flip side is that the 148 plus 140 pathway is probably the most common resistance pattern with RAL failures especially if virologic failure has been ongoing for some time in the presence of RAL. The 155H mutation may show up early but in some patients the virus undergoes a transition to the 148/140 path.  These viruses did not respond as well to 572.  There was a decrease in HIV RNA in most of the patients that had 148 plus one or more mutations but the effect was modest (mean of 0.72 and an approximate median of about 0.5 log10). 572 at the 50 mg once a day dose is not likely to have a major impact in individuals with these viruses unless there were several other active agents that could be combined in an optimized regimen.  The logical question (which was asked by Bernard Hirschel) was what about a higher dose. 572 has been well tolerated and the dose response curves that have been generated would suggest that a higher dose should have a greater activity.  The VIKING study is now enrolling a cohort 2 – which will test 50 mg twice daily.  Hopefully this second cohort will show us whether more robust responses can be seen again viruses that have moved down the 148 pathway.  An additional clinical point that could be taken from the VIKING results are that individuals who are on raltegravir and who are failing should probably be moved to an alternative regimen or have their raltegravir stopped if at all possible.  Prolonged failure in the face of raltegravir selective pressure may push the virus to greater cross-resistance to 572.

 

NRTI-sparing
The last topic I want to touch on just briefly is the topic on NRTI-sparing regimens, in particular for treatment naïve patients. It had never really occurred to me but if you look at the DHHS guidelines there is not one single NRTI-sparing first-line regimen listed in any category (Preferred, Alternative, Acceptable, possibly Acceptable).  One could argue that perhaps we just don’t need NRTI-sparing regimens in first line therapy, but as our patient’s age and the very long term toxicity of nucleosides becomes apparent there is great pressure to keep looking. 
IAC produced several pilot studies of NRTI-sparing regimens.  The largest, called PROGRESS, compared LPV/r plus RAL both BID with LPV/r plus TDF/FTC over 48 weeks in over 200 subjects.  The bottom line is that the 2 treatment arms looked very similar virologically and there were very few virologic failures with resistance in either arm.  A strong word of caution though is that the baseline viral load was very low, less than 20,000 c/mL (remember ECHO and THRIVE had a median baseline VL of 100,000).  LPV/r plus RAL may be a very good NRTI sparing regimen but it needs to be challenged in patients with higher viral load.  In addition, the lipid levels were higher on the NRTI-sparing arm probably reflecting the lipid lowering effect of TDF.  In this modest sized short term study there were not major differences in toxicity.
The small pilot SPARTAN study which combined RAL and atazanavir (ATV) unboosted both BID provides a contrast to PROGRESS.  While the overall results were similar in this arm to ATV/r plus TDF/FTC at 24 weeks (2:1 randomization with 63 vs. 30 subjects in each arm), there were more subjects on RAL plus ATV who had virologic failure with resistance testing results. There were 11 VL failures (VL > 50 at week 24) on the RAL arm, 8 had baseline VL greater than 250,000 c/mL, 6 had HIV RNA > 400 copies and had resistance testing and 4 had RAL resistance mutations. In contrast, while there were 8 “virologic failures” on the ATV/r TDF/FTC arm only 1 had a viral load greater than 400 and that patient had no resistance mutations.  Bilirubin levels were also higher on the RAL/ATV arm and there was no suggestion that ATV concentrations on that arm were sub-optimal.  I think we need more data on the RAL plus PI (preferably boosted) in high viral load patients before we venture to far down this path in the clinic, despite the PROGRESS results. 
One other NRTI-sparing regimen that was tested was maraviroc (150 mg once daily) plus ATV/r compared to a reference arm of ATV/r plus TDF/FTC. Again this was a small study with 60 patients per arm.  At 24 weeks a greater proportion of patients on the NRTI arm were less than 50 c/ml (89%) though this is a very high number for ATV/r TDF/FTC – much higher than was seen in the CASTLE study for example.  MVC plus ATV/r had 80% < 50 c/mL at 24 weeks so perhaps this may be an NRTI sparing regimen to test in a larger number of patients.  The number of subjects with baseline VL > 100,000 in this study was small but MVC plus ATV/r seems to do similarly in low and high VL groups.
I don’t think NRTI-sparing is ready for clinic prime time on a large scale but perhaps there are situations where it is appropriate and again switching once suppressed may be a safer approach but to date we only have pilot type data in this setting too.  A large trial of DRV/r plus raltegravir compared to DRV/r plus TDF/FTC in treatment naïve patients is about to start in Europe and it should provide some answers – though we will have to wait for some time to see these results.

Fw: Hot Topics at The Body’s “Ask the Experts” Forums

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August 10, 2010 Visit the Forums “Hot Topics” Library Change/Update Subscription

MIXED-STATUS COUPLES

 Can You Help Me Ease My New Partner’s Mind?
I’m a 40-year-old woman and I contracted HIV from my husband 16 years ago. We divorced about two years ago and I’ve just met someone new. I told him I was HIV positive before we had sex to give him the choice of whether or not to be with me. He says he really likes me but has several fears and concerns, which we’ve discussed. Is there anything else I can tell him from a medical perspective that might ease his mind?

 How Can I Deal With Rejection?
I recently dated my first-ever HIV-negative partner. At the beginning, he said he was fine with my being HIV positive, but when we broke up he threw my HIV status back in my face. I don’t want to limit myself to just dating poz guys, but I don’t think I can keep submitting myself to rejection. I’ve started pulling back from any kind of romance or intimacy — I’m becoming a monk sexually and an icicle emotionally. How can I deal with rejection while continuing to date?

BEYOND HIV/AIDS MEDICATIONS

 Will Milk Thistle Interact With My HIV Meds?
I’m taking Combivir (AZT/3TC) and Sustiva (efavirenz, Stocrin) right now. Is it safe to take milk thistle along with these HIV meds to prevent future liver problems? Are there any studies planned looking at this herbal supplement?

 Effective Supplement — or “Placebo Effect”?
How can people taking supplements tell the difference between real benefits and “the placebo effect”? How long does the placebo effect last?

Also Worth Noting: Visual AIDS

Image from the August 2010 Visual AIDS Web Gallery
“Debutantes” 1992; Frank Moore

Visit the August 2010 Visual AIDS Web Gallery to view our latest collection of art by HIV-positive artists! This month’s gallery, entitled “The Infidels’ Hallelujah,” is curated by Guy Bérubé and Francesco Corsaro.

LIVING WITH HIV/AIDS

 Missing Work Due to Side Effects: What Are My Options?
I take Atripla (efavirenz/tenofovir/FTC) and side effects have caused me to miss many days of work. I’ve used all my paid time off and extended sick leave. Should I give notice and just start collecting unemployment?

HIV/AIDS TREATMENT & SIDE EFFECTS

 I’m Even Resistant to Experimental Treatments: What Can I Do Now?
For about a year I participated in a clinical trial of ibalizumab (TNX-355), an entry inhibitor in development for HIVers with resistance to many meds. In the beginning my virus became undetectable, but then it developed resistance to the study drug. I’m now taking Aptivus (tipranavir), Norvir (ritonavir), Trizivir (AZT/3TC/abacavir) and Viread (tenofovir). Can you weigh in on the progress of current studies of meds for treatment-experienced HIVers?

 How Do I Figure Out What’s Causing My Chronic Fatigue?
I have been battling chronic fatigue since I was diagnosed with HIV 10 years ago. I’ve had a number of stressors in my life recently, and I’ve started taking vitamin B12. I’ve also been managing wheat, sugar and dairy allergies through diet modification. I should be feeling great but I’m not. What else can I do?

 Why Am I Gaining So Much Weight on My New HIV Med Regimen?
I started taking Isentress (raltegravir) and Truvada (tenofovir/FTC) a month ago. When I started taking this regimen I had a CD4 count of zero and my viral load was well over 300,000. Since starting this regimen I have gained about 23 pounds. Do you have any idea why this would happen, since I haven’t changed my eating or exercise habits?

More Questions About HIV/AIDS Treatment & Side Effects:

OTHER HEALTH ISSUES & HIV/AIDS

 Could Reinfection Have Caused My Boyfriend’s Lymphoma?
My boyfriend was recently diagnosed with lymphoma. He’s on HIV meds with an undetectable viral load, while my viral load is 70,000. We’ve been having unprotected sex for three months. Is it possible that I reinfected him with my detectable virus, and that that eventually caused his lymphoma?

 HIV Positive and Diabetic: How Can I Reduce My Need for Diabetic Treatment?
I’m HIV positive with a great CD4 count and an undetectable viral load, and I have type 2 diabetes. My blood sugar levels aren’t well controlled and my doctor wants me to start injections, but I want to stay with oral meds. I don’t exercise and weigh 280 pounds. What do you suggest I do?

Connect With Others
Can Anyone Recommend Books or Stories About Living With HIV?
(A recent post from the “I Just Tested Positive” board)

I’m a 25-year-old gay male newly diagnosed with HIV. Was wondering if anyone could recommend any books? I’m looking for inspiring stories, personal experiences, etc. Anybody know of anything good? — strong3

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HIV/STD TRANSMISSION

 Should My PEP Regimen Be the Same as the Person’s to Whose Virus I Was Exposed?
If a condom breaks while I’m having sex with an HIV-positive guy who’s on HIV meds with an undetectable viral load, and I can find out what meds he’s taking, should my post-exposure prophylaxis (PEP) regimen match the meds he takes?

 I Know Oral Sex Carries Low Risk for HIV — but What About Other STDs?
I’m a 50-year-old man who usually plays it safe, but I recently gave a stranger a blow job and didn’t use a condom. He had no visible sores and didn’t cum in my mouth. I understand my HIV risk from this encounter is very low, but if he had syphilis or another STD (sexually transmitted disease), would bumps or sores have to be present in order for me to become infected?

STRANGE BUT TRUE

 Head-Over-Heels Infected?
I scratched myself on the leg with the heel of my own shoe, and the scratch is red and puffy. The day before, I remember stepping in disgusting gutter water and on dirty cement, and I even visited my uncle in the hospital. If there was HIV-infected blood on something I put my heel on, and then 20 hours later I scratched myself with that heel, is there any chance I could get HIV this way?

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Activist Central

 President Obama: Address the ADAP Crisis!

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 NMAC Asks for Your Help Ending S.B. 1070; Promoting Comprehensive Federal Immigration Reform

 Action Alert: Help Homeless AIDS Activist Get Into Housing Today

What am I going to do now, Nelson?

What am I going to do now, Nelson?
Aug 6, 2010
Hi Nelson, I hope all is well. Last year you told me about the trial with ibalizumab at ACRIA and I received the meds for about 1 year. In the beginning of thet trial the virus became undectadable but then it started to go up again and they took me out of the study. I was in the trial for about 1 year. My doctor changed my regimen to recycle meds…I’m resistant to all of them. I am now on Aptivus, Viread, Norvir and Trizivir. Do you know of any other trials in NYC? Thanks for your help.
Response from Mr. Vergel


I am so sorry that your virus developed resistance to ibalizumab (Taimed’s intravenous CD4 monoclonal antibody that may be given once every two weeks).
I am working with ACRIA and two San Francisco doctors in setting up a small expanded access pilot to combine two investigational agents by early summer 2011, but we are still waiting for data. But it is not a done deal. However, one of the drugs may be ibalizumab.
GSK-ViiV are testing a second generation integrase inhibitor (GSK572) in phase II now and we are really hoping it can help people with raltegravir resistance. Some preliminary data show that it may help those with certain integrase mutations. GSK is also testing two non nucleosides in early phase 2. So, it will take at least 8 months to know where we are going with these agents.
AVEXA, an Australian company that has an interesting nucleoside, may be back in the picture after their board reconsidered not dropping their drug due to activist pressure. I am following that drug closely also.
BMS seems to have an entry inhibitor but they are a company that does not like to share information with treatment activists, so it has been a challenge to get them to tell us anything. It is unfortunate that in 2010 we still have this lack of communication going (but they are rare among companies).
Progenics also had a once a week subcutaneous entry inhibitor that looks very exciting. They are also a company that has refused to meet with treatment activists. They are small and may not understand the power that activists have in the present to help advocate for new drugs.
Koronis (http://www.koronispharma.com/KP1461forHIV.html) also has an interesting nucleoside that works very differently than the ones we have right now, but they have not tested it in people like you with a failing regimen.
Some of these companies may or may not agree to provide drug in a compassionate manner for one patient (but remember that you need at least two new active drugs to avoid functional monotherapy). But if your doctor wants to ask them, the FDA has set up a way to do so provided that the companies are willing to help. The FDA procedure is http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm163982.htm
It is getting harder and harder for companies to justify spending money on new drugs that attack new targets since they perceive the treatment experienced market to be too small to justify the investment. And many doctors are telling them that people like you and me do not exist anymore. So, it is more important than ever not to fall asleep in treatment activism.
I am focusing a lot of my energies in helping people like you who may fall through the cracks if we do not provide at least two drugs at the same time that your virus does not have resistance to.
One more thing. This is anecdotal but I have seen people in salvage’s viral load go down a lot with good daily prophylaxis for herpes (acyclovir, Valtrx, or Famvir) (http://www.aidsmap.com/page/1431675/) twice a day and also with the use of an antibiotic called minoxycline ( http://www.aidsmap.com/page/1438246/), plus their HIV drug regimen. Talk to your doctor about these if you are not taking them already.
Keep in contact with me. I will keep everyone informed through this column as things progress.
Hang in there and please keep in touch with me.
Nelson