Author - Nelson Vergel

Low-dose growth hormone therapy reduces inflammation in HIV-infected patients

Randomized controlled trial

Lindboe JB, et al. Infect Dis (Lond). 2016 Nov-Dec.


Lindboe JB1, Langkilde A1, Eugen-Olsen J2, Hansen BR2,3, Haupt TH1, Petersen J1,4, Andersen O1,3.

Author information

  • 1a Optimed, Clinical Research Centre 056, Copenhagen University Hospital Hvidovre , Hvidovre , Denmark ;
  • 2b Clinical Research Centre 056, Copenhagen University Hospital Hvidovre , Hvidovre , Denmark ;
  • 3c Department of Infectious Diseases , Copenhagen University Hospital Hvidovre , Hvidovre , Denmark ;
  • 4d Department of Biostatistics , University of Copenhagen , Copenhagen , Denmark.


Infect Dis (Lond). 2016 Nov-Dec;48(11-12):829-37. doi: 10.1080/23744235.2016.1201722. Epub 2016 Jul 15.


BACKGROUND: Combination antiretroviral therapy (cART) has drastically increased the life expectancy of HIV-infected patients. However, HIV-infected patients exhibit increased inflammation and 33-58% exhibit a characteristic fat re-distribution termed HIV-associated lipodystrophy syndrome (HALS). Recombinant human growth hormone (rhGH) has been tested as treatment of HALS. Low-dose rhGH therapy improves thymopoiesis and fat distribution in HIV-infected patients and appears to be well tolerated. However, since high-dose rhGH is associated with adverse events related to inflammation, we wanted to investigate the impact of low-dose rhGH therapy on inflammation in HIV-infected patients.

METHODS: Forty-six cART-treated HIV-infected men were included in the HIV-GH low-dose (HIGH/Low) study: a randomized, placebo-controlled, double-blinded trial. Subjects were randomized 3:2 to 0.7 mg/day rhGH, or placebo for 40 weeks. rhGH was self-administered between 1 pm and 3 pm. The primary outcome of this substudy was changes in inflammation measured by plasma C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR).

RESULTS: Both CRP (-66%, p = 0.002) and suPAR (-9.7%, p = 0.06) decreased in the rhGH group compared to placebo; however, only CRP decreased significantly. The effect of rhGH on inflammation was not mediated through rhGH-induced changes in insulin-like growth factor 1, body composition, or immune parameters.

CONCLUSION: Daily 0.7 mg rhGH treatment for 40 weeks, administered at nadir endogenous GH secretion, significantly reduced CRP. The effect does not appear to be mediated by other factors. Our findings suggest that low-dose rhGH treatment may minimize long-term risks associated with high-dose rhGH therapy.

New Bill Mandates Coverage of HIV Lipodystrophy Treatments

Ben Klein, a Senior Attorney from speaks about the new bill approved in the state of Massachusetts in Aug. 2016 that mandates several insurance carriers in that state to reimburse cost for HIV related lipodystrophy therapies and how activists can advocate for similar bills in other states.

California is also trying to get a similar bill approved.

California May Require Insurance Companies Cover Lipodystrophy for Poz People

Senator Scott Wiener (D-San Francisco) introduced an Equality California sponsored bill called HEAL (“Help End Antiretroviral-related Lipodystrophy”) that will require insurance companies and government programs to cover medical treatment for those suffering from the condition.

“The early generation of anti-retroviral medications saved thousands and thousands of HIV survivors’ lives, yet they scarred many survivors with the disfigurement caused by lipodystrophy,” Senator Wiener said in a statement. “Many long-term HIV survivors continue to struggle with this side effect, with both physical and psychological ramifications. The failure of our private insurance and public health programs to cover lipodystrophy correction surgeries for long-term HIV survivors is both unacceptable and discriminatory. It’s time to ensure that these long-term HIV survivors receive the healthcare they need, including correction of this debilitating health condition.”


How to Protect Your Mitochondria

The   topic   of   mitochondrial   damage   is gaining more and more press as a potential side effect of anti-HIV medication. Simply put, the mitochondria are the “energy factories” of the cell —the tiny, rod-shaped structures, or “organelles,”

within each cell responsible for producing roughly 90 percent of all the energy that cell needs in order to survive. The number of mitochondria in a particular cell is based upon the energy needs of that cell and can range from 200 to 2,000.

About 80 percent of the energy generated by mitochondria is created through a cellular aerobic (meaning requiring oxygen) process called oxidative phosphorylation, which creates adenosine triphosphate, or ATP. Creating ATP includes an intricate series of steps that involve five multi-subunit enzymes or complexes. Each complex has a different nutritional and chemical need in order to function properly. This is important to remember when exploring the nature of treatment for mitochondrial damage.


As mitochondria produce ATP, they simultaneously yield reactive oxygen species (ROS), which are harmful free radicals that circulate throughout the cell, the mitochondria, and the body, causing more damage. The circulation of ROS leads to the activation of reactive nitrogen compounds, which  in  turn  induce,  or  activate,  genes  in  the DNA that are associated with many degenerative diseases such as Alzheimer’s, Parkinson’s, strokes, and multiple sclerosis. The term “mitochondrial toxicity,” therefore, is a misnomer and actually refers to the process of mitochondrial damage.


The DNA for each mitochondrion (mtDNA) remains unprotected within the membrane of the mitochondrion itself. In comparison to the DNA in the nucleus of the cell (nDNA), mtDNA is easily damaged by free radicals and the ROS that they produce. Freely floating mtDNA lacks protective measures associated with nDNA, and therefore mtDNA suffers from multiple mutations.


It has been estimated that this lack of protective measures results in mutations to mtDNA occurring 10 to 20 times more frequently than mutations to nDNA. The mitochondria that are produced have decreased ability to function, resulting in the inability to utilize fatty acids for energy production, and therefore a decreased ability to store fat in muscle tissue.


In order for mitochondria to reproduce themselves, a specific enzyme called gamma- DNA-polymerase, or “pol gamma” is required. Many medications have been found to interrupt pol gamma. Studies suggest that virtually all the nucleoside analog reverse transcriptase inhibitors (NARTIs)—such as AZT, 3TC, ddI, ddC, d4T, and abacavir—interrupt pol gamma to some extent. This disruption prevents the transport of long-chain fatty acids from being transported the membrane wall into the mitochondria, where they are used as primary fuel and energy sources. As a result, fatty acids are dysfunctionally deposited and accumulated in muscle tissue. Without the cell’s  main  source  of  energy,  the  number  of newly formed mitochondria drops, and therefore, cell function decreases, and possibly even cells die (or apoptosis). Symptoms developed by an individual would depend upon the type of cell affected. However, the most common symptom is generalized, overall fatigue.


Test tube (in vitro) studies have demonstrated that ddC, ddI, and d4T are the most potent inhibitors of pol gamma, although the other NARTIs exert some influence as well. To date, researchers have not studied the extent of mitochondrial damage when anti-HIV medications are combined, which is standard practice for most individuals currently on anti-HIV therapy. Moreover, the effect of combining NARTIs with other anti-HIV medications, such as protease inhibitors, is not known.


However, one study demonstrated a reduction in number of mitochondria produced in a cell in people taking d4T. Data from yet another small study suggested that HIV-positive individuals taking any of the NARTIs had up to 44 percent fewer mitochondria per cell than those individuals who are either not taking NARTIs or are HIV- negative. One study demonstrated that those taking AZT had significant depletion of mitochondrial DNA in muscle tissue.


In a study examining the number of mitochondria per cell, participants were separated into four groups: (1) HIV-positive individuals who were on medications and had fat loss/wasting, (2) HIV-positive individuals on medications without signs of fat redistribution, (3) HIV-positive individuals who had not taken anti-HIV drugs and (4) individuals who were HIV-negative. The group with the greatest decrease in mitochondria in cells was  the  group  with  fat  loss/wasting,  followed by the HIV-positive group on medications yet without signs of lipodystrophy. The latter two groups showed no difference in the number of mitochondria. The conclusion drawn is that anti- HIV medications do interfere with the production and lifecycle of mitochondria.


It has been postulated that mitochondrial damage  is  always  present,  but  the  question  is to what extent. Mitochondrial damage is poorly diagnosed, and when symptoms do occur, they can run the range from mild, to severe, to life- threatening. For instance, common symptoms include fatigue, muscle weakness (myopathy), peripheral neuropathy, and pancreatitis. However, some researchers suggest that regardless of HIV serostatus, damage to mitochondria can be a possible factor in low platelet count (thrombocytopenia), anemia, and low neutrophil count (neutropenia). Furthermore, there is a significant link between damaged and dysfunctional mitochondria and the development of Type II diabetes in adults, again, regardless of HIV serostatus.


With early enough detection, many of these symptoms and conditions are reversible by altering therapy. This may include stopping medication, or significantly reducing dose. However, people considering such a course of action should first consult with their healthcare provider to identify the specific cause for the symptom.


How can mitochondrial damage be detected? The easiest way is through a blood test that measures lactate levels in the blood. Lactate is a natural byproduct from the breakdown of glucose and fat in the mitochondria. The sore and tired feeling in the muscles following rigorous exercise is a result of the body shifting to “anaerobic respiration” that leads to a buildup of lactic acid. When the mitochondria are damaged, lactate levels rise in the bloodstream and lead to lactic acidosis. This increase in the acidity in the blood is life threatening and must be dealt with immediately. Lactic acid level in the blood should be measured (without a tourniquet, if possible) after a person has been resting for at least 5 minutes, and has refrained from vigorous activity and alcohol consumption for 24 hours.


Early symptoms of lactic acidosis are severe fatigue, nausea, vomiting, shortness of breath, abdominal pain, rapid weight loss, muscle cramps and aches, muscle numbness and tingling, and rapid and progressive muscle weakness. As the severity  increases  and  lactate  levels  rise  over 5 mmol/liter (the normal value is less than 2), mitochondria lose their ability to produce energy, leading to potentially irreversible organ damage and death.


At present, there are no comprehensive studies presenting clear treatment strategies for dealing with mitochondrial damage associated with HIV. Extrapolation can, however, be made from  the  knowledge  available  about  treatment of mitochondrial damage associated with other diseases. First and foremost is to identify and treat the cause. For many, however, this option may be limited. If it is true that the main associated factors are the NARTIs, then switching to another therapy might be suggested. Eliminating this entire class of HIV medication from treatment options leads to a whole host of medical and health-related issues. It does seem, at this time, that ddI, ddC, and d4T are the most potent inhibitors of pol gamma. This should  be  considered  for  those  suffering  from mitochondrial damage. The availability of Viread (tenofovir) has provided a good alternative to other NRTIs for many people, and Viread does not appear to affect mitochondrial function.


Finally, several nutrients have been studied for their ability to decrease damage to the mitochondria. In the current literature regarding mitochondrial damage and HIV therapies, some mention has been made about carnitine, coenzyme Q10,  and  riboflavin  (B2).  Most  of  these  are being studied in isolation and not in conjunction with one another. Although the approach is to determine whether or not each particular nutrient is beneficial in the treatment of mitochondrial damage, the flaw in this approach stems from the fact that each of the five complexes in the oxidative phosphorylation process requires different and varying nutrients simultaneously. Other nutrients that support mitochondrial function are alpha lipoic acid, NAC (N-acetyl-cysteine), vitamin E, and essential fatty acids, to name a few.


Carnitine is a natural substance found in food, mainly meat and dairy products, that can be quickly absorbed in the small intestines. The standard daily American diet contains roughly between 10 to 100 milligrams of carnitine. The body can synthesize carnitine from the essential amino acid, lysine, with vitamin C, niacin, vitamin B6, iron, and the amino acid methionine as necessary cofactors. Carnitine is vital to the life of the cell since it is required for the transport of long-chain fatty acids into the mitochondria. Regarding supplementation, two forms of carnitine have been used, either L-carnitine or acetyl carnitine. Studies show that supplementation with L-carnitine decreases the percentage of both CD4 and CD8 cells undergoing cell death (apoptosis.)


Furthermore,        supplementation        with L-carnitine has been successfully used in the treatment of mitochondria-induced muscle weakness and degeneration. Studies with patients taking AZT reveal low levels of carnitine found in their muscle tissues. Several studies explored the use of 6 grams of L-carnitine daily intravenously. The   results   revealed   a   reduction   in   serum triglyceride  levels,  an  increase  in  peripheral blood   mononuclear   cell-associated   cermainde (an intercellular messenger of apoptosis), and a decrease in tumor necrosis factor (a cytokine that is produced as a result of infection, which intensifies viral replication). Another study, in which HIV- positive patients with severe neuropathy were given daily intramuscular injections of 1 gram of acetyl-carnitine (the form of carnitine more easily absorbed in the intestines), showed decrease in patient report of pain and improved movement and mobility. Overall, carnitine is necessary to keep mitochondria alive and functioning well, thereby resulting in proper nerve and muscle function, fatty-acid synthesis, and energy production.


No  RDA  (recommended  daily  allowance) has been established for carnitine. Studies range in the amounts used for mitochondrial and neurological benefits. No side effects have been reported, but this author has had patients report slight gastrointestinal pain within a half hour of taking carnitine orally. Current trends recommend between 1,000 to 4,000 mg of L-carnitine or acetyl carnitine in divided doses daily. Because carnitine is an amino acid, it is best absorbed on an empty stomach.


Carnitine works synergistically with another nutrient, the fat-soluble vitamin-like compound called coenzyme Q10 (CoQ10), also known as ubiquinone. CoQ10 is an essential factor in the electron transport chain, the pathway from which ATP and metabolic energy is derived, which occurs within the mitochondria. CoQ10 is a strong antioxidant that resides in the lipid membrane surrounding the mitochondria and protects it against free radical damage. Although the body can generate its own CoQ10, supplementation has been shown to be warranted in persons with HIV. CoQ10 is synthesized in the cells of every living organism in nature. The body produces CoQ10 in  a  17-step  process  that  requires  riboflavin (B2), niacinamide (B3), pantothenic acid (B5), pyridoxine (B6), cobalamine (B12), folic acid, vitamin C, and other trace minerals. Due to its complex and intricate requirements, nutritional deficiencies  with  any  one  of  these  vitamins can disrupt mitochondrial energy production. Generally,  symptoms  of  CoQ10  deficiency affect cardiovascular health in the form of congestive  heart  failure,  stroke,  arrhythmias, high blood pressure, mitral valve prolapse, and cardiomyopathy. Additionally, lack of energy, gingivitis, and overall weakened immunity are symptoms of CoQ10 deficiency.


Many medications directly deplete the body of CoQ10. While antiretrovirals have not been studied for their effect on CoQ10 levels, both antiretrovirals and antibiotics, such as Bactrim and Dapson, deplete the body of the B-vitamin family. Other medications, specifically cholesterol- lowering medications, anti-hypertensive medications like beta-blockers, and some tricyclic antidepressants like amitriptyline (at times used for treatment of neuropathy) all directly deplete the body of CoQ10, and thereby negatively impact the mitochondria. Studies of HIV-positive individuals who are either on antiretroviral medications or are drug naive reveal CoQ10 deficiencies.


Supplementation with CoQ10 has shown decreased incidence of opportunistic infections and improved immune parameters, measured by a reduction in symptoms such as night sweats, fever, diarrhea, weight loss, and lymphadenopathy.


Again, no RDA has been established for CoQ10;   yet,   current   recommendations   range from 30 to 120 mg per day, depending upon the severity of symptoms and health status. No side effects have been reported for CoQ10.


Riboflavin or B2, is a water-soluble vitamin, that, like other B vitamins, is not stored well in the body so must be ingested daily. Riboflavin belongs to a category of yellow colored pigments called flavins (the reason urine changes color when taking B vitamin supplements). When riboflavin interacts with phosphoric acid it becomes a part of two essential enzymes. These enzymes are necessary for the conversion of carbohydrates to energy in the form of ATP within the mitochondria of the cell. Furthermore, deficiencies in riboflavin will exacerbate CoQ10 deficiencies. For these reasons,


riboflavin supplementation has been considered in the treatment of mitochondrial damage. Many medications, such as antiretrovirals, antibiotics, oral contraceptives, and the tricyclic antidepressant noritriptiyline result in direct riboflavin deficiencies. No major studies have demonstrated a direct improvement in mitochondrial health with supplement of riboflavin. However, since multiple cofactors are required in energy production in the mitochondria, studies of riboflavin alone may be misguided.


Typical symptoms of frank riboflavin deficiencies are inflamed mucous membranes, chelosis (cracks in the corners of the mouth), soreness and burning of lips, tongue, and mouth, burning, itching and tearing eyes, eczema of skin and genitals, light sensitivity, dry and itching scalp, nerve damage, depression and hysteria.


The recommended daily allowance (RDA) for riboflavin is approximately 1.7 mg per day. For pregnant women, nursing mothers and heavy exercises, higher doses are recommended. Several studies have used dosages in the range of 2 to 100 mg per day.


Several other nutrients, which are beneficial to the health of the mitochondria and immune system, need mention here. The first, alpha lipoic acid,  is  a  powerful  antioxidant.  Alpha  lipoic acid is found in highest concentration within the mitochondria, and helps protect against damage to the cell’s membranes. In vitro, alpha lipoic acid has been demonstrated to inhibit tumor necrosis factor, NF-kappa B, the on-off switch for activation of HIV, and tat gene activity In Europe, alpha lipoic acid has been used successfully for the treatment diabetic neuropathy, leading to its study in the efficacy of treatment for HIV-related neuropathy either as a result of medication or the virus itself. Because of its ability to cross the  blood  brain  barrier,  alpha  lipoic  acid  has been recommended as a potential treatment for cognitive disorders as well. Alpha lipoic acid has been shown to heal liver cells, decrease elevated liver enzymes, and lower high blood glucose. An added benefit of alpha lipoic acid is its ability to recycle vitamin C and vitamin E, and to increase blood levels of glutathione. No RDA exists for alpha lipoic acid, but use ranges between 100 to 1,200 mg per day. However, one study postulated that high doses (above 1,200 mg daily) may result in thrombocytopenia, decrease in platelet counts, but this has not be replicated. Standard practice often recommends 200 mg twice a day.


One of the most significant benefits N-acetyl- cysteine (NAC), the sulfur-containing amino acid, is its reported ability to raise glutathione levels. Glutathione is the primary antioxidant system within  the  body,  thus  aiding  the  body  against free radical damage. While the literature is still unclear as to whether or not supplementation with oral glutathione will in fact raise tissue stores of glutathione, the majority of studies do conclude that NAC supplementation will raise glutathione levels.  Many  medications  and  substances deplete glutathione, such as acetaminophen, sulphamethoxazole    (Bactrim),    and    alcohol, and protease inhibitors deplete liver stores of glutathione, thus the recommendation that those with HIV infection refrain from using large amounts of acetaminophen.


Additionally,  NAC  supplementation  leads to a “relative” increase in CD4 cells and a reduction  in  HIV-1  replication  in  stimulated CD4 cells. Dosage suggestions vary considerably with ranges between 1,000 mg to 8,000 mg per day having been studied. Side effects of higher dosages include gastrointestinal distress that can be alleviated by taking NAC with food. Standard protocols suggest between 1,000 mg and 3,000 mg per day in divided doses.


Finally, dietary fat has a major impact on the  health  of  mitochondria.  Trans-fatty  acids, fat sources from hydrogenated and partially hydrogenated vegetable oils directly affect the membranes through which fats must be shuttled to be used by the mitochondria for energy. The greater the amounts of trans-fatty acids in the diet, the less fluid can easily pass through. As mentioned earlier, the production of ATP involves


five multi-subunit complexes. Studies suggest that trans-fatty acids might inhibit ATP production by inhibiting complex V in the process. Therefore, diets high in saturated fats and trans-fatty acids are to be avoided in order to prevent damage to or improve the function of mitochondria. Rather, essential  fatty  acids  such  as  flaxseed  oil  and fish oils should be recommended ensure healthy membranes surrounding mitochondria.


Mitochondria are sensitive organelles whose function and health can be easily disrupted. In searching for “treatments” for mitochondrial damage, many researches continually focus on one nutrient or one substance to restore balance. Since the ATP system is complex and requires a large number of nutrients, such a singular search will often fail to yield a significant result. For this reason, a series or group of nutrients needs to be explored. L-carnitine (acetyl-carnitine), CoQ10, and B vitamins would be an excellent starting point for someone suffering with mitochondrial damage. Since all nutrients have multiple benefits, those interested in expanding their protocol should consult about any supplementation program with a qualified healthcare provider well versed in HIV medications as well as diet and nutrition.


HIV Activists Seek to Accelerate Development of Immune Enhancing Therapies for Immunologic Non-Responders.



For more information:

Richard Jefferys

Michael Palm Basic Science, Vaccines & Cure Project Director
Treatment Action Group


Nelson Vergel

Program for Wellness Restoration






HIV Activists Seek to Accelerate Development of Immune Enhancing Therapies for Immunologic Non-Responders.


Dialogues with FDA, scientists and industry encourage consideration of orphan drug designations for therapies to help the immunologic non-responder population and exploration of novel endpoints to reduce the size of efficacy trials.


November 30, 2016 – A coalition of HIV/AIDS activists are calling for renewed attention to HIV-positive people termed immunologic non-responders (INRs), who experience sub-optimal immune system reconstitution despite years of viral load suppression by antiretroviral therapy. Studies have shown that INR patients remain at increased risk of illness and death compared to HIV-positive people who have better restoration of immune function on current drug therapies. Risk factors for becoming an INR include older age and a low CD4 count at the time of treatment initiation. To date, efforts to develop immune enhancing interventions for this population have proven challenging, despite some candidates from small companies showing signs of promise.


“We believe there is an urgent need to find ways to encourage and accelerate development of therapies to reduce the health risks faced by INR patients,” stated Nelson Vergel of the Program for Wellness Restoration (PoWeR), who initiated the activist coalition. “For example, Orphan Drug designations[i] could be granted to encourage faster-track approval of promising therapies.  These interventions may eventually help not only INRs but also people with other immune deficiency conditions”.


Along with funding, a major challenge for approval of any potential therapy is proving its efficacy. While INRs face significantly increased risk of serious morbidities and mortality compared to HIV-positive individuals with more robust immune reconstitution, demonstrating a reduction in the incidence of these outcomes would likely require expensive and lengthy clinical trials involving thousands of individuals. Activists are therefore encouraging the US Food & Drug Administration (FDA), industry and researchers to evaluate potential surrogate markers of efficacy such as relative improvements in clinical problems that may be more frequent in INR patients, such as upper respiratory infections, gastrointestinal disease, and other health issues.


“Given the risks faced by INR patients, every effort should be made to assess whether less burdensome pathways toward approval are feasible, without compromising the regulatory requirement for compelling evidence of safety and efficacy”, said Richard Jefferys of the Treatment Action Group.


The coalition is advocating that scientists, biotech and pharmaceutical companies pursue therapeutic candidates for INRs. For example, while gene and anti-inflammatory therapies for HIV are being assessed in the context of cure research, there is also evidence that they may have potential to promote immune reconstitution and reduce markers associated with risk of morbidity and mortality in INR patients. Therapeutic research should also be accompanied by robust study of the etiology and mechanisms of suboptimal immune responses.


“While there is, appropriately, a major research focus on curing HIV, we must be alert to evidence that candidate therapies could have benefits for INR patients, and be willing to study them in this context”, argued Matt Sharp, a coalition member and INR who experienced enhanced immune reconstitution and improved health and quality of life after receiving an experimental gene therapy.


The coalition has held an initial conference call with FDA to discuss the issue. Minutes of that meeting are available online.


The coalition is now aiming to convene a broader dialogue with various drug companies on the development of therapies for INR patients. Stakeholders who are interested in becoming involved are encouraged to contact coalition representatives.



[i] The purpose of the Orphan Drug Act is to incentivize the development of treatments for rare conditions. For more information, see:



New HIV Medications Being Studied in 2017

Antiretroviral treatment – where we are now / New HIV Drugs & Treatments
Joseph J. Eron MD Professor of Medicine University of North Carolina at Chapel Hill
The CROI meeting in Seattle this year was again a terrific mix of basic, translational, clinical and epidemiological research. This year perhaps we are seeing more clinical data than we have seen in the last few CROI with some terrific late breaker presentations.
Antiretroviral treatment – where we are now
There were two very nice poster presentations from Thibaut Davy-Mendez who is a PhD candidate at UNC. Working with data from our UNC CFAR HIV Clinical Cohort he described trends in antiretroviral treatment and HIV resistance, prevalence and incidence over the last several years.
In his presentation on Increased Persistence Of Initial Art With INSTI-containing Regimens [Davy et al Abstract 465] he demonstrates the dramatic shift to initial therapy with integrase- inhibitor based regimens in the last several years. By 2014 over 80% of new treatment starts were with INSTI-based regimens in our cohort. This shift has resulted in substantial differences in persistence of first-line therapy (by that we mean how long someone stays on their first regimen before switching or discontinuing their anchor agent) and also in the rates of virologic failure. Davy-Mendez showed that the median time to moving away from or stopping INSTI-based therapy was greater than 6 years and that patients on an INSTI-based therapy were significantly and substantially less likely to stop or switch from INSTI-based therapy compared to NNRTI based therapy (HR = 0.49 (0.35, 0.69). Those patients started on INSTI-therapy were also less likely to experience virologic failure. These data are only likely to improve as much of the data were captured before single tablet integrase inhibitor therapy became the norm.
Davy-Mendez also looked at prevalence of resistance in our cohort in Low Prevalence Of HIV Drug Resistance With Modern Agents [Davy et al Abstract 483]. In this analysis he did two things: first he looked at prevalence of resistance in all patients who were active in the cohort in a given year. All previous and current resistance tests were used and resistance was counted even if the patient’s viral load was suppressed. For example if in 2006 a patient has viremia and a resistance test that show NRTI, NNRTI and PI resistance that information is captured for that year. If in 2007 she suppressed on raltegravir, etravirine and darunavir/r (like many patients did) that resistance burden still exists in the cohort even though she is suppressed on therapy. The resistance remains in every year she stays in the cohort. The second analysis looks only at resistance in patients who have viremia in a given year and the resistance assessment includes all past tests (cumulative resistance). So if our patient listed above rebounds in 2010 and has INSTI-resistance documented her cumulative resistance would include 4 classes. You can think of this like an iceberg of resistance. The first analysis is the whole iceberg and gives you an idea of the total resistance burden – hopefully most in underwater (i.e. suppressed). The second analysis is the part of the iceberg that is visible – so circulating resistance in viremic patients. Patients who are lost to follow-up, move away or die no longer contribute to the resistance analysis in the subsequent year. Perhaps a picture is worth 1000 words

This figure is the whole iceberg (notice the y-axis only goes to 60%). We see that the burden of resistance in our cohort (and I suspect most cohorts in the US) is declining. PI and NRTI resistance has declined substantially as has 1-, 2- and 3-class resistance. Fortunately integrase resistance remains very low, less than 5% of patients in the cohort (recall that we are a referral center for much of North Carolina so we may be enriched for “Viking” like patients1).
The tip of the iceberg looks like this:

Here the story is a little different – the proportion with resistance is higher and the downward trends are not nearly as obvious (except for maybe protease inhibitor resistance). The good news is that viremic patients are a small proportion of our total patient populations (approximately 10% or less). We also looked at patient who started therapy with modern preferred regimens (2007 to 2014). In this group emergent resistant virus was even much less common – with resistance to at least one drug in 2 classes emerging in only 5% of 685 patients and resistance to one or more drugs in 3 classes emerging in only 1%. However resistance is likely to be with us as long as we have HIV and we are treating people who are – like us – human.
PS – Huldrych Gunthardt and the Swiss do these types of analyses really well and I urge you to read the two papers by Scherrer et al cited here2,3.
We need a new drug or a new strategy – or do we??
Some exciting new antiretroviral treatment data were presented at CROI at several levels of development.
Novel combination of InSTI and NNRTI for Maintenance of Suppression
There were two large phase III randomized antiretroviral treatment trials presented.
In the SWORD 1 and 2 studies a novel combination of an INSTI (dolutegravir) and an NNRTI (rilpivirine) were studied in patients suppressed on a first or second regimen with no previous history of resistance or virologic failure [Libre et al Abstract 44LB]. This study is the first successful large comparative study of a two-drug combination maintenance therapy that did not include a boosted protease inhibitor (or a nucleoside analogue). Over 1,000 participants were randomized to either stay on their initial 2NRTI plus anchor agent regimen or switch to dolutegravir 50 mg and rilpivirine 25 mg once daily. Fifty-four percent of participants were on a NNRTI at baseline, approximately 26% were on a PI and 20% were already on an INSTI based regimen. Most were on TDF (approximately 72%). The study was open label and patients with hepatitis B were excluded. Ninety-five percent of participants in each arm were < 50 c/mL at 48 weeks and only 3 participants (<1%) and 6 participant (1%) had virologic non-response in the DTG/RPV and continuation ART arms respectively. There were more discontinuations due to AE in the experimental arm (16 (3%) vs. 2 (<1%)), which is not too surprising given that the median time on stable ART at the time of randomization was > 4 years and that the study was open-label and a new adverse event may have been more likely to be attributed to the experimental therapy than to chronic stable therapy. Supporting this conjecture is that fact that overall AE and serious AE occurred at similar rates in the two arms, more AE’s were attributed as drug related in the DTG/RPV arm. Most were grade 1-2. Only two participants in each arm met protocol defined virologic failure (for some reason termed “confirmed virologic withdrawal”). One participant on the DTG/RPV arm had emergence of a virus with a mixture at K101K/E, which is an NNRTI resistance mutation. However this mutation did not confer phenotypic resistance to RPV, the patient’s rebound viral load was > 1,000,000 (suggesting non-adherence) and the participant re-suppressed on DTG/RPV before therapy could be changed. No integrase resistance mutations were identified.
Implications: Overall an excellent result – high success, minimal virologic non-response and no clear resistance emergence in over 500 patients treated with this simple, low milligram, likely to be co-formulated treatment that will have some but not many drug-drug interactions and no renal clearance. However this was a very conservative study. Participants could have had no virologic failure, no history of transmitted K103N, PI or NRTI mutations despite the fact that the regimen should not be impacted by NRTI or PI resistance and likely not transmitted K103N, which was allowed in the switch studies using rilpivirine/TDF/FTC . Participants with more than one previous treatment switch, even if they remained suppressed, were also excluded. So one might ask, “Who will receive this combination?” Pill size will be important for some patients. Patients on boosted PI who would like simplification would also likely consider this – though many of these patients have already switched therapy. Prior to the introduction of TAF this would have been perhaps an optimal therapy for patients with modest renal dysfunction but if patients are already on a TAF based therapy perhaps only those with more substantial renal compromise (eGFR in 30 mL/min range) would be considered for switching. Many clinicians have patients suppressed on therapy who are on more cumbersome therapy or therapy with potential for longer term toxicity who have NRTI or PI mutations. Such patients might benefit from a switch to DTG/RPV though this was not a group that was studied in SWORD 1 and 2. Whether a such a patient should switch will likely be an individual patient/clinician decision based on the overall risk:benefit ratio of that patient.
We should also note that another simple two-drug combination DTG plus 3TC might also be considered in some of these switch situations. A small non-comparative study of switching stably suppressed patients to DTG/3TC was also presented at CROI. In that study, called Lamidol [Joly et al Abstract 458], patients suppressed on 2 NRTI and a third drug first had their third drug switched to dolutegravir for 8 weeks and if they remained suppressed they entered second phase in which participants had their two NRTI simplified to 300 mg of 3TC. Of 104 participants who entered the second part of the study 101 remained suppressed at 48 weeks with only one virologic failure. This two-drug combination is being studied in two very large (700 participants each) actively enrolling randomized trials, called Gemini 1 and 2, in treatment naÏve patients ( We won’t have results of these trials for over a year but clinicians may also be thinking about this relatively simple two-drug combination as a switch strategy in the appropriate clinical context.
CROI: SWORD 1 & 2: Switch to DTG + RPV Maintains Virologic Suppression Through 48 Weeks, a Phase III Studyg – (02/16/17)
New Drug – Coming soon
The first phase III study of the NNRTI doravirine, called DRIVE, was presented in Seattle [Molina J-M et al Abstract 45LB]. Doravirine is a once daily NNRTI that does not have an interaction with proton pump inhibitors, did not appear to have substantial CNS side-effects in a phase II study compared to efavirenz4, has activity against the most common NNRTI-resistance mutations5 and will likely have limited drug-drug and food interactions6. This study, in treatment naÏve participants, compared doravirine to darunavir/ritonavir each patient with either TDF/FTC or ABC/3TC in a randomized double blind fashion. The 766 participants who entered had a choice of NRTI (88% chose TDF/FTC) and had to take 4 pills (doravirine 100 mg with DRV and RTV placebos or doravirine placebo with active DRV and RTV each plus the 2 NRTI tablet). The results at 48 weeks demonstrated that doravirine was non-inferior to DRV/r with 84% vs. 80% < 50 c/mL in the FDA snapshot analysis. CD4 cell count responses were good and similar between the two arms and doravirine responses were consistent in the populations of participants with baseline HIV RNA > 100,000 and > 500,000 c/mL. There were 19 protocol defined virologic failures in the doravirine arm and 24 in the DRV/r arm. In addition, some patients also left the study with HIV RNA > 50 c/mL who had not yet met the definition of virologic failure. Genotype resistance testing was attempted in both these groups. Not surprisingly no participants developed PI or NRTI resistant virus in the DRV/r arm. Remarkably, only a single patient in the doravirine arm (out of 383) developed drug resistance mutations that led to doravirine and FTC/3TC resistance, suggesting a higher barrier to resistance emergence for this NNRTI. Rash and neuropsychiatric adverse events occurred at similar rates in the two arms and overall AE’s were similar with numerically less diarrhea in the doravirine arm (14 vs. 22%). There were relatively few Grade 3 or 4 laboratory abnormalities and not surprisingly the lipid profile of doravirine was more favorable than with DRV/r.
Implications: Cross study comparisons are fraught with potential bias – though it is difficult not to make them. The overall result of suppression at 48 weeks (84 vs. 80%) in the DRIVE study is lower than we have seen with recent integrase inhibitor based studies in which 48 week suppress rates on the integrase inhibitor arms are in the 90% range7-10. One issue with the current study is the regimens were blinded and participants had to take 4 pills a day which may have impacted the retention rate on the study. Approximately 10% of participants in each arm left the study for reasons other than an adverse event and prior to reaching protocol defined virologic failure. Further data are expected as a head-to-head comparison with fixed dose combination efavirenz/TDF/FTC is fully accrued and should give initial results soon and a switch study from efavirenz-based therapy is recruiting ( Given the results of this first study, doravirine with 2 NRTI is non-inferior to one of the DHHS first-line initial regimens for treatment naÏve patients (DRV/r) at 48 weeks. However, most guidelines and most initial treatment starts in many clinics in the developed world are moving toward or have already embraced integrase inhibitors as the anchor for first line therapy. Where doravirine will fit into that equation is not clear. If data consistent with a favorable CNS profile continue to accrue that could be an advantage of this drug and it will likely be approved as a single agent and will therefore have the flexibility to be partnered with any of the two-drug NRTI combinations. According to Merck a fixed dose formulation with TDF and FTC is in development.
CROI: Doravirine in Non-Inferior To Darunavir+Ritonavir in Phase 3 Treatment-Naive Trial at Week 48g – (02/16/17)
Paul Sax and his colleagues presented Phase II data on the newest integrase inhibitor, bictegravir [Sax P, el al Abstract 41]. Bictegravir is a very promising agent. This INSTI has in vitro and in vivo potency similar to dolutegravir and very favorable pharmacokinetic characteristics that allow once a day dosing with resulting trough levels many fold higher than the protein adjusted IC95. Bictegravir has activity against most INSTI-resistant viruses that are selected for by raltegravir and elvitegravir but, to date, we have seen very little clinical data about this agent despite the fact that four phase III studies are now fully enrolled. In Paul’s presentation we saw the first comparative “longer-term” 48-week data in a randomized comparison to dolutegravir both paired with TAF/FTC in treatment naÏve patients. This is a phase II study so the number of participants in each arm is small and with a 2:1 randomization there were 65 participant randomized to the bictegravir arm and only 33 participants randomized to dolutegravir. Both treatments did very well and after 48 week 97% of participants randomized to the bictegravir arm were < 50 c/mL by the FDA snapshot analysis. Only 2 participants were not successful. One discontinued due to a skin-related adverse event and the other was a virologic failure. There were only 3 virologic failures in the 98 randomized patients – none developed resistance.
Implications: What makes bictegravir potentially special is that it does not require boosting to have excellent PK exposure and it is in development as a co-formulation with TAF and FTC with a total milligram burden of < 300 mg – likely translating into a small pill size. Like dolutegravir drug-drug interactions should be relatively minor. It does look like from Paul Sax’s presentation that bictegravir will increase creatinine slightly presumably through a similar mechanism to dolutegravir and cobicistat. The interaction of bictegravir with metformin appears to be less than with dolutegravir [Zhang H et al Abstract 40].
The proof, of course, will be in the results of the Phase III trials. In treatment naÏve patients there is a comparison similar to the Phase IIB trial – bictegravir/TAF/FTC fixed dose combination (FDC) vs. dolutegravir plus TAF/FTC in a blinded (3 pills each) randomized trial of approximately 645 participants. Also in treatment naÏve participants the second trials compares bictegravir/TAF/FTC vs. Dolutegravir/ABC/3TC both fixed dose combinations, again blinded (2 pills a day) and randomized (approximately 630 participants). Then there are two switch studies for suppressed patients. One enrolling patients on boosted atazanavir or darunavir with either TDF/FTC or ABC/3TC and randomizing participants to stay on the boosted-PI 2 NRTI regimen or switch to bictegravir/TAF/FTC FDC. This is an open-label study with approximately 520 enrolled participants. The second switch studied enrolled patients on dolutegravir with ABC/3TC and randomized them in a blinded fashion to dolutegravir/ABC/3TC FDC or bictegravir/TAF/FTC FDC. Over 560 participants were enrolled. All these studies will reach their primary endpoint sometime in 2017. We look forward to those results. If this fixed dose integrase inhibitor combination is successful then we will have an integrase-based single tablet without boosting, which can be used in hepatitis B and without HLA B5701 testing.
CROI: Randomized Trial of Bictegravir or Dolutegravir with FTC/TAF for Initial HIV Therapyg – (02/16/17)
CROI: Bictegravir Dissociation Half-life from HIV-1 G140S/Q148H Integrase-DNA Complexesg – (02/28/17)
Ibalizumab is a monoclonal antibody that has been in development for many years with the first clinical study published eight years ago11. The antibody blocks HIV replication by binding to the second domain of CD4 molecule preventing HIV entry. Ibalizumab has activity against both R5 and X4 viruses and does not appear to affect CD4 cell function. In its present formulation it has to be administered by IV infusion. At CROI we saw the 24-week results of the very small (40 patient) phase III study [Lewis S et al Abstract 449LB]. The study follows the basic design for antiretrovirals being developed for patients with limited treatment options. At screening patients were required to have resistance to at least one drug in three different antiretroviral classes and have a least one fully active agent to add to an optimized background regimen. Patients with highly resistant virus (35% resistant to multiple agents in 4 or more classes) were enrolled. After entry participants were observed over a 7 day period. They then received an IV infusion of ibalizumab as functional mono-therapy and the results at 7 days is actually the primary endpoint of the study. Treatment is then optimized at day 7 and in this study some patient were able to use a second novel agent fostemsavir, which is an oral attachment inhibitor. Ibalizumab infusion continues 2 weeks along with the optimized background and the 24 week results were presented. Forty patients were enrolled with mean CD4 cell count of 150 cells/mm3 at baseline. 83% had > 0.5 log10 decline and 60% had a > 1.0 log10 decline over 7 days. The longer term, 24 week results, reflected the extensive pre-entry resistance with only 43% having an HIV RNA < 50 c/mL at week 24 and in participants with < 50 CD4 cells/mm3 at baseline less than 20% were < 50 c/mL at 24 weeks. Participants who received fostemsavir actually had numerically poorer outcomes than those who had an active agent available in an existing class though no formal statistical analysis was undertaken. Ibalizumab appeared safe. Eight of the 9 participants who discontinued had < 50 CD4 cells/mm3 at baseline (4 were deaths).
Implications: There are patients in our clinics who will likely benefit from ibalizumab. They mirror the patients enrolled in this trial with highly antiretroviral drug resistance virus and limited treatment options. Fortunately these patients are uncommon and are typically patients who have been in care for prolonged periods and received sequential mono-therapy over the last 3 decades as we learned how to use antiretrovirals effectively and new agents appeared one at a time. At present the administration requires IV infusion and if approved by the FDA will likely be labeled as an every 2 week infusion given the phase III study design. The antibody has relatively modest potency with average short-term log reduction in the 1.0 log10 range. Intramuscular injections every 2 weeks and every 4 weeks are being explored [Lin HH el al Abstract 438] and appear to give similar exposure. According to the Theratechnologies website an FDA NDA filing is planned.
PRO-140 and UB-421
Clinical data on two other monoclonal antibodies that block HIV-1 entry into cells were also presented at CROI. One, PRO-140 has been around in development for a very long time. This antibody binds to CCR-5 and block entry of R5 viruses (like the small molecule maraviroc). The study presented was a long-term follow-up of a subset of patients, with R5 virus, who were on successfully suppressive oral therapy and had switched to single-agent therapy with this antibody delivered as a weekly subcutaneous injection [Lalezari et al Abstract 437]. The original study started with 31 patients who were treated for 12 weeks and 16 of these participants were entered into long-term follow-up. Over two years, 10 of the sixteen maintained suppression on this single self-administered SQ agent. One participant has been suppressed for 41 weeks. The other 9 have been suppressed for > 105 weeks at the time of the presentation. We were told that the 6 patients who did not stay suppressed did not rebound with X4 or dual tropic virus and that the reason for rebound was likely drug exposure but the primary data were not presented on the poster. There were very few adverse events that were attributed to the medication with a single unrelated serious adverse event and no severe adverse events in the 16 participants.
Implications: Obviously these are very preliminary data in a select population (remember that it is really 10 of 31 who started the mono-therapy > 2 years earlier) and there is no control group. On the other hand two years on a single drug (even if given subcutaneously) is an eye-opening result and I spoke with one of the investigators who said his patient tolerated the therapy very well and are happy with self-administering the antibody. One could imagine that patients who are on complex oral therapies, that don’t include maraviroc and who have R5 virus using an archive DNA assay could try this approach that would be completely orthogonal [completely different – not overlapping – so in this case no chance of selecting for cross resistance] to their oral regimen. The risk, of course, would be viral rebound but presumably restarting oral therapy would be successful.
A study to test this hypothesis is ongoing. In PRO140_CD03, 300 participants with HIV RNA suppressed on oral antiretroviral therapy who have CCR5-tropic HIV-1 infection are being enrolled and will receive PRO 140 as long-acting, single-agent maintenance therapy for 48 weeks. On that study is listed as enrolling.
There is also a standard phase III study (like the ibalizumab study described above) for patients with highly drug resistant virus that is also enrolling (Pivotal Combination Study: PRO140_CD02).
CROI: PRO 140 Single-Agent Maintenance Therapy for HIV-1 Infection: A 2-Year Updateg – (03/01/17)
One other monoclonal antibody that is being studied in HIV-1 infected people was presented. This antibody, UB-421, like ibalizumab binds to the CD4 molecule blocking HIV entry although it binds to the first domain of CD4 not the second domain which may have implications for CD4 cell function. The authors presented a study, similar to the PRO-140 study in which patient who were suppressed on oral therapy were switched to intravenous infusion of UB-421 either weekly (14 participants) or every other week (15 participants) for 8 infusions [Wang CY, et al. Abstract 450BLB]. Remarkably all the participants remained suppressed for the 8- and 16-week periods respectively and then stayed suppressed or re-suppressed (several chose not to restart oral therapy right away) when oral therapy was restarted. This monoclonal antibody is at a much earlier stage of development than either ibalizumab or PRO-140 and there are no open studies listed on In the study presented there was an effect on the level of T regulatory cells in the blood of the participants suggesting there may be some effect on T-cell trafficking which will be important to better understand if this antibody moves forward in development.
Capsid Inhibitor
Winston Tse from Gilead presented data on perhaps one of the most novel classes of antiretrovirals to come along in a while, capsid inhibitors [Tse W, et al Abstract 38]. The capsid is what coats the HIV genetic material and sits under the viral envelope. It is essential in several steps in the HIV life cycle including viral assembly, uncoating after entry (which can’t be done haphazardly or the virus goes down the proteasome drain) and transport to the nucleus of the pre-integration complex. Targeting the capsid is tough because it is not an enzyme that has a specific binding site but could be rewarding given that multiple steps in the life cycle may be blocked. The prototype capsid inhibitor presented is extremely potent (pico-molar range – 10-12 concentration) and targets a very conserved region so that resistance variants may be hard to select for (though NOT impossible) or may have diminished fitness. This class of capsid inhibitors may have a very long half-life in people. In an animal model (rat) a single sub-cutaneous injection sustained levels above paIC95 for 10 weeks. These are early days however and no data are available yet for in vivo models of HIV/SIV infection (i.e. monkeys or humanized mice) and no human PK data were presented. We are hearing more about very long acting agents and, at least for treatment, we are likely to need two or more with similar half-lives to combine to create an effective therapy. Capsid inhibitors may be a step in that direction. However, this agent is in early pre-clinical development and has not been given to humans yet even in single dose PK studies. An oral form may be difficult to develop.
CROI: Discovery of Novel Potent HIV Capsid Inhibitors with Long-Acting Potentialg – (02/16/17)
Finally we did see first presentations of early pre-clinical data on two drugs in existing classes. One was a NRTI (GS-9131)[White K, et al Abstract 436]. You might ask, “Why would we need another NRTI?” This NRTI had impressive in vitro activity against very resistant nucleoside/tide resistant variants including variants with resistance to tenofovir and variants with multiple thymidine analogue mutations (TAMS). Only the uncommon 151 mutation complex led to an increase fold-change in vitro. The presenter, Kirsten White, stated that this drug is scheduled to begin PK studies in people and one could imagine combining this NRTI with other agents, such as a second generation integrase inhibitor, to be used in patients with drug-resistant virus. There was also a presentation on a new protease inhibitor [Link J, et al Abstract 433]. This agent was presented predominantly because in vitro suggested a high barrier to resistance and animal PK data and human liver microsome data suggested limited metabolism and a relatively long half-life that would likely mean that this PI would NOT require boosting with ritonavir or cobicistat and therefore might have the potential for co-formulation. Early days – no human studies have started yet.
CROI: GS-9131 is a Novel NRTI with Activity Against NRTI-Resistant HIV-1g – (02/23/17)
CROI: Novel HIV PI with High Resistance Barrier and Potential for Unboosted QD Oral Dosing – (02/28/17)
CROI Citations
Davy T, Napravnik S, Zakharova O et al. Increased Persistence Of Initial Art With INSTI-containing Regimens. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 465
Davy T, Brunet L, Napravnik S, Zakharova O et al. Prevalence Of HIV Drug Resistance With Modern Agents. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 483
Libre J, et al. SWORD 1 & 2: Switch to DTG + RPV Maintains Virologic Suppression Through 48 Weeks, a Phase III Study. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 44LB
Joly V, Burdet C, Landman R, et al, PROMISING RESULTS OF DOLUTEGRAVIR + LAMIVUDINE MAINTENANCE IN ANRS 167 LAMIDOL TRIAL. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 458
Molina J-M, Squires K, Sax P, et al. DORAVIRINE IS NON-INFERIOR TO DARUNAVIR/R IN PHASE 3 TREATMENT-NAÏVE TRIAL AT WEEK 48. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 45LB
Sax P, DeJesus E, Crofoot G, et al. RANDOMIZED TRIAL OF BICTEGRAVIR OR DOLUTEGRAVIR WITH FTC/TAF FOR INITIAL HIV THERAPY. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 41
Zhang H, Custodio J, et al. CLINICAL PHARMACOLOGY OF THE HIV INTEGRASE STRAND TRANSFER INHIBITOR BICTEGRAVIR. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 40
Lewis S, Fressel J, Emu B, et al. LONG-ACTING IBALIZUMAB IN PATIENTS WITH MULTI-DRUG RESISTANT HIV-1: A 24-WEEK STUDY. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 449LB
Lin HH, Lee S, Wang NC, et al. INTRAMUSCULAR IBALIZUMAB: PHARMACOKINETICS, SAFETY, AND EFFICACY VS IV ADMINISTRATION. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 438
Lalezari J, Dhody K, et al. PRO 140 Single-Agent Maintenance Therapy for HIV-1 Infection: A 2-Year Update. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 437
Wang CY, Wong WW, Tsai HC, et al. A Phase 2 Open-Label Trial of Antibody UB-421 Monotherapy as a Substitute for HAART. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 450LB
Tse W, Link J, Mulato A, et al. Discovery of Novel Potent HIV Capsid Inhibitors with Long-Acting Potential. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 38
White K, Margot N, Stray K, et al. GS-9131 is a Novel NRTI with Activity Against NRTI-Resistant HIV-1. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 436
Link J, Cato D, Moore M, et al. Novel HIV PI with High Resistance Barrier and Potential for Unboosted QD Oral Dosing. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 433
Other References:
1. Eron JJ, Clotet B, Durant J, et al. Safety and Efficacy of Dolutegravir (DTG) in HIV-1 Treatment-Experienced Subjects With Raltegravir-Resistant Virus: 24-Week Results of the VIKING Study. J Infect Dis. Dec 7 2012.
2. Scherrer AU, von Wyl V, Yang WL, et al. Emergence of Acquired HIV-1 Drug Resistance Almost Stopped in Switzerland: A 15-Year Prospective Cohort Analysis. Clin Infect Dis. May 15 2016;62(10):1310-1317.
3. Scherrer AU, Yang WL, Kouyos RD, et al. Successful Prevention of Transmission of Integrase Resistance in the Swiss HIV Cohort Study. J Infect Dis. Aug 01 2016;214(3):399-402.
4. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc. 2014;17(4 Suppl 3):19532.
5. Feng M, Sachs NA, Xu M, et al. Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations. Antimicrob Agents Chemother. Apr 2016;60(4):2241-2247.
6. Anderson MS, Gilmartin J, Cilissen C, et al. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 2015;20(4):397-405.
7. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. Mar 31 2014.
8. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. Nov 7 2013;369(19):1807-1818.
9. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. Jun 27 2015;385(9987):2606-2615.
10. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. Jun 30 2012;379(9835):2439-2448.
11. Jacobson JM, Kuritzkes DR, Godofsky E, et al. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother. Feb 2009;53(2):450-457.

Top Ten Testosterone Replacement Monitoring Tips

Nelson Vergel, author of Testosterone: A Man’s Guide ( and founder of and, talks about what he thinks are the most important 10 things that all men on testosterone replacement therapy should know to maximize benefits and minimize side-effects. For questions for Nelson, please register on and post them on the forum page. For more detailed information about what blood test parameters are important to monitor while on testosterone replacement therapy, read:

Testosterone Replacement Blood Test Targets and Their Management

For blood tests to buy to monitor your testosterone replacement, check this panel:

TRT MALE Hormone/Wellness Follow Up Panel


Why Has Only One Person Been Cured of HIV in 10 Years?

In 2006, Timothy Brown, an American living in Berlin,  was on antiretroviral therapy with good viral suppression when he developed leukemia and required bone marrow transplants after other treatment failed.

His doctor in Berlin, Gero Hütter, MD, had the idea to use bone marrow from a donor with a double CCR5-delta-32 mutation, meaning the stem cells were missing the CCR5 co-receptor that most types of HIV use to enter T-cells.

Brown underwent intensive chemotherapy that killed off his cancerous immune cells, nearly killing him in the process. The donor cells then rebuilt a new immune system that was resistant to most HIV.

Although Brown stopped ART the day he received the first of two bone marrow transplants, his HIV did not return. Despite 10 years of poking and prodding—repeatedly testing his blood, immune cells, gut tissue, and everywhere else they could manage to look—researchers have not been able to detect replication-competent HIV anywhere in Brown’s body.

Dr Gero Hütter and others have tried to replicate Brown’s case with little luck.  Here is what happened to other people exposed to the same procedure:

The pursuit of a cure for HIV infection has become a central plank of the overall research portfolio, and this has been officially underpinned by the revised HIV/AIDS priorities announced by the U.S. National Institutes of Health (NIH) in 2015.The NIH has cited the goal of developing a cure for HIV/AIDS as one of five high-priority areas for HIV/AIDS research.  There are several studies undergoing at the moment to get to  the cure of HIV within our lifetime.  The Treatment Action Group has summarized the current study pipeline in this report:

Research Toward a Cure and Immune-Based and Gene Therapies

Here are some trials attempting to flush HIV out of its hidden places (reservoirs):

Here are studies related to HIV vaccines:


Hopefully, one day we will have a cure for HIV that is practical, affordable and non-toxic that can cure over 36 million people living with HIV around the world. The race is on!

How Researchers Are Now Trying to Cure More HIV+ People

We are constantly reading headlines about the latest HIV cure. After years of being exposed to these inflamed news reports, we may get desensitized to the fact that there is actually progress being made in that field. Ever since Timothy Brown was proven to be cured, the search for a cure for HIV that is accessible worldwide has intensified. There is more funding now as different research groups compete to get there first. But we have had set backs that have taught us important lessons.

I decided to interview two leading HIV Cure research advocates on a Google hangout (webcast) to pick their brains about what has happened to people who have entered HIV cure studies. In particular, I wanted to get an update on the outcome with people who have been exposed to stem cell transfers, stem cell/CD4 cell manipulation, and those who seemed to control the virus after stopping antiretrovirals. I hope you will find this webcast as enlightening as I did!


Richard Jefferys began working in the HIV/AIDS field in 1993 at the nonprofit AIDS Treatment Data Network in New York City. Since that time he has written for the International AIDS Vaccine Initiative’s IAVI Report and, in late 2001, he joined the Treatment Action Group (TAG) where he now directs the Michael Palm Basic Science, Vaccines and Cure Project. The project covers the pathogenesis and immunology of HIV infection and advocates for the development of immune-based therapies, effective vaccines, and a cure.

Robert Reinhard serves as the Community Liaison and a Steering Committee member of the CanCURE research consortium, a Canadian national team grant to understand the role of myeloid/macrophage cells in HIV persistence and cure strategies. He is also a research associate and community team member in the University of Toronto laboratory of Mario Ostrowski developing a therapeutic HIV vaccine. Robert is a member of the International AIDS Society Towards an HIV Cure Industry Collaboration working group.


Exercise Tips for Health, Lean Muscle and Reduced Fat

As a nutrition and exercise expert, in this video I share what I’ve learned in the past 27 years of exercising to combat HIV-related body changes, fatigue and mental outlook with great exercise tips that will save everyone time and costly mistakes.

You can also read my tips in this article.

Reducing HIV-Related Inflammation: Safety Study of Ruxolitinib

Dr Vincent Marconi talks about his study “Evaluating the Safety and Tolerability of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults” which is currently looking for volunteers. For more information about the study or how to join it, call us at 206-744-8883 or email us at…
Dr Vincent Marconi received his MD at the Johns Hopkins School of Medicine in 2000. He then received training in Internal Medicine and Infectious Diseases at the Brigham and Women’s Hospital and the Massachusetts General Hospital of Harvard Medical School. Currently, he is Professor of Medicine for the Division of Infectious Diseases and Professor of Global Health at the Rollins School of Public Health. In 2014, he became the Director of Infectious Diseases Research at the Atlanta Veterans Affairs Medical Center. Dr Marconi sees patients at both the Infectious Disease Program Ponce Clinic (part of the Grady Health System) as well as the Infectious Disease Clinic of the Atlanta VA Medical Center. He has co-authored over 90 scientific articles.

To read the transcript of this interview, click here