Disco-dosing and PrEP

Status-post residency, I decided to subscribe to The New England Journal of Medicine in an attempt to look awesome and scholarly in front of my neighbors.  Since I began receiving the journal at the beginning of July, the weekly issues have remained stacked on top of my "hope chest", aka ottoman next to the sofa, accumulating dust for the most part and serving as the occasional coffee rest.

Volume 367 Number 5 happened to attract my attention today; it focused on articles pertaining to pre-exposure prophylaxis for HIV.  To give some background, POST exposure prophylaxis (for HIV) has been around for a long time.  If a person is exposed to HIV or at high risk of having been exposed, ie unprotected sex, rape, needle stick, the same medications used to treat HIV infection, antiretrovirals, can be used to reduce the risk of transmission or seroconversion to an active infection in the exposed person.  Post-exposure prophylaxis is well established in medicine, but recently there has been an increase in studies looking at use of antiretrovirals, ARVs, BEFORE a person engages in an activity that increases risk of HIV infection; I'm talking about sex.

The iPrEX study opened the flood gates; it found reduced risk of HIV infection when men-who-have-sex-with-men, or MSM, took tenofovir-emtricitabine before engaging in high risk behavior.  The aptly named "disco-dosing" was done hand in hand with education on transmission and condom use.  The CAPRISA study released shortly after found a 39% reduction in HIV transmission when women in South Africa used a tenofovir vaginal gel before sexual intercourse.  The medicated vaginal gel allowed women to take their health into their own hands especially in a culture that gave women little right to demand that their partners or husband wear a condom.  Strangely, tenofovir vaginal gel failed to show any benefit in the VOICE study.

Three studies were published together in the August 2nd issue of NEJM comparing Truvada (emtricitabine-tenofovir) and placebo used daily for pre-exposure prophylaxis in heterosexual persons in Africa.  The Partners PrEP study compared the use of emtricitabine-tenofovir or tenofovir alone to placebo in serodiscordant couples in East Africa, where one partner had a positive HIV status while the other was negative, and followed patients for a year.  Relative to placebo, daily tenofovir decreased the risk of HIV transmission by 67% while daily use of emtricitabine-tenofovir reduced risk 75%.  Patients taking emtricitabine-tenofovir had an increased risk of neutropenia, GI upset, and fatigue but no difference was seen in death or worsening kidney function (tenofovir can cause kidney toxicity).  I was surprised that the majority of seronegative patients at baseline were men (62%).

The FEM-PrEP study evaluated the use of daily Truvada in HIV-negative, higher-risk women in Kenya, Tanzania, and South Africa.  High risk was defined as woman whom had had at least one vaginal sex act in the past two weeks or more than one sex partner in the past month.  All women were given access to condoms and other medications for contraception.  While the study was stopped early due to futility, the investigators saw high pregnancy rates in both groups, including in women who were "taking" oral contraceptives.  In addition, adherence rates were self reported as "high" and pill counts showed study drug adherence of 88%, while random drug-level testing showed less than 1/3 of patients were actually taking the study medication.  Failure to show benefit may have been secondary to low adherence rates.

The TDF2 study, also published in the August 2, 2012 edition of The New England Journal of Medicine, compared the use of daily Truvada to placebo in sexually active, heterosexual adults in Botswana, which has the second highest HIV prevalence in the world.  All patients were given condoms and counseling on HIV in addition to other HIV prevention services and all women enrolled also had to agree to use effective contraception during the course of the study.  There was a 62.2% risk reduction for patients taking Truvada.  It is interesting to note that while the FEM-PrEP study only enrolled "high risk" sexually active females, this study had no inclusion criteria for behavioral risk but did show a significant risk reduction of HIV infection.

Breakdown:
These studies will be instrumental in developing guidelines on populations where pre-exposure prophylaxis, or "disco-dosing" will be most beneficial in preventing infection.  While the iPrEX and CAPRISA studies showed benefit to chemoprophylaxis of HIV, many questions remain.  In my opinion, starting a daily antiretroviral in an otherwise healthy person puts them at risks of drug toxicities and is an additional burden on the health-care budget.  The TDF2 study showed that heterosexual sexually active adults in Botswana could significantly reduce their risk of HIV with daily Truvada, yet it does not seem economically feasible to place all adults aged 18-39 in Botswana on the drug and furthermore encourages the formation of resistant strains to what is the first line NRTI combination for the treatment of HIV.

While these studies are beneficial in establishing cohorts that may benefit most from chemoprophylaxis, the results are conflicting, as seen in comparing the TDF2 study to the FEM-PrEP study and the CAPRISA study to the VOICE study.  In addition to balancing risk of drug-induced toxicity to risk of contracting HIV, no studies as of yet have established the length of time a person needs to stay on PrEP.  While emtricitabine and tenofovir are two of the better tolerated ARVs, all studies showed increased nausea, vomiting, dizziness, and drowsiness in patients taking the study medications.  It may be difficult to convince otherwise healthy adults to add an additional medication to their daily routine that may come with a side effect burden.

To conclude, pre-exposure prophylaxis is undoubtably an exciting advance in HIV world, but despite growing numbers of studies, I just haven't been able to buy in quite yet.

References:
Grant RM et al.  Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM 2010; 363(27):2787-99.  (iPrEX)

Baeten JM et al.  Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.  NEJM 2012; 367(5):399-410. (Partners PrEP)

Van Damme L et al.  Preexposure prophylaxis for HIV infection among African women.  NEJM 2012; 367(5):411-22. (FEM-PrEP)

Thigpen MC et al.  Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.  NEJM 2012; 367(5):423-34.  (TDF2)

Cohen MS, Baden LR.  Preexposure prophylaxis for HIV- where do we go from here? NEJM 2012; 367(5):459-61.

Wisdom from Farmer

It is very expensive to deliver poor quality health care to poor people in a rich country
-the man, the myth, the legend: Dr. Paul Farmer

After jumbling times at the International AIDS conference and realizing after the fact that I had missed a presentation by both Paul Farmer, a physician that co-founded Partners in Healthcare, AND Elton John, I was relieved to know that Paul Farmer was coming to Gallup, New Mexico to present.

Paul Farmer has written extensively on inequalities on a global scale in health care, as I have only read one of his books (now signed!) "Infections and Inequalities" I will be primarily drawing from this, his talk, and personal experience.  What I found fascinating about "Infections and Inequalities" is that it provided data to support truths that I had already experienced.  At the risk of sounding like a cliche 20-something year old American girl (which I am), it took a trip to a third world country for me to see that the problems of Africa are not so distant from the problems at home.  I saw the same disease states in the homeless population of Boston as I did in Tanzania, namely tuberculosis and HIV.

Paul Farmer remarks in his book that an analysis of the cause of death for the worlds wealthiest fifth is dramatically different than that of the world's poorest fifth, where the leading cause of death is not heart disease or cancer, but rather infectious disease.  Shocking still is that likelihood of contracting an infection (or dying from infectious disease) is not determined by the country of origin, but rather from a person's socioeconomic status.

To return with my opening quote from today's lecture, I believe that Dr. Farmer intended to weigh quality of care with budget, an issue that I am confronted with daily, if not hourly, at an Indian Health Service hospital.  When funds are limited, how can we ensure that we are delivering the high quality care that every patient has a right to while staying within budget restrictions?

Dr. Farmer explained that currently, much of the money going into HIV/AIDS programs is being funneled into establishing primary care programs, which benefit not only HIV positive patients, but the other members of their communities of well.  When chronic disease states are well managed, the cost of care decreases as a result of decreased complications.  The issue with weighing finances with quality of care is that large funds are not typically allotted to establishing good primary care.  Dr. Farmer emphasized the importance of establishing structures, like the hospital or clinic itself, training caregivers, and providing community health reps as vital in improving care quality.  Community health reps are people that go on home visits to ensure not only that the patient is taking medications, but also that everything else in the patient's environment is not contributing to worse health outcomes.

Providing poor quality care increases health expenditures as it does not decrease complications of chronic and acute disease states.  A dear friend of mine in Tanzania became ill, was hospitalized for two weeks, and subsequently died.  I returned to Tanzania to see her family and to pay back the hospital bill.

My friend's mother, Bibi (KiSwahili word for grandmother) had already sold her cow in order to make the payment.  I agreed to pay her back, only to discover that the cost of a two week hospitalization at a rural hospital was ~$275 USD.  The difference in cost between this and a 2 week hospitalization in the U.S. is astounding.  When tourists fall ill, they are most often airlifted to the Nairobi hospital, which seems to be considered to provide the highest quality of health care within Eastern Africa.  The cost of care at this facility, in addition to transport to this hospital, would have undoubtedly exceeded $275, but would my friend have lived? In healthcare, as in most things, you get what you pay for.

Paul Farmer emphasized that many things comprise the health of a patient.  He believes that poverty, political unrest, and unemployment among other things are disease states.  Changing a patient's situation in life has dramatic effects on their health.  Many interventions we can make, such as sending out community health reps or CHR, can make an impact through helping the patient to find a more stable living situation or even help to repair things in the patient's home (the example he gave was of a CHR sent out to provide education on diabetes but instead helped to repair a patient's roof).  Ensuring a patient's nutrition status can dramatically change their health status as well, to paraphrase Dr. Farmer:

I am excited to say that I will soon be receiving a nobel prize for discovering that the cure for malnutrition is something called "food".

Simple, but stable, interventions can go a long way.

AIDS 2012

The first time that I remember hearing about HIV/AIDS was the day the principal of my elementary school retired in 1993.  We were at an assembly and the principal was speaking, giving a resignation speech.  I was paying more attention to my feet than anything else but as he finished, I looked up and saw that all of the adults in the room, including my mother, were crying.  I asked her what was wrong and she told me he had AIDS.  It would be a long time before I really understood what this meant.  (correction: my mother informs me she does not remember this happening).

Flash forward: I am a college graduate working in a multidisciplinary clinic caring for HIV positive patients and I have been given the opportunity to attend the International AIDS Society conference in Washington DC.  It is absolutely incredible how far medicine has progressed in less than 10 years.

In remembrance of 1993: there was only one drug available for treatment.  Zidovudine, which was first marketed in 1987, is a nucleoside reverse transcriptase inhibitor or "NRTI".  It is the only anti-retroviral drug currently available in intravenous formulation and is still used in patients today.  However, in light of the most current guidelines, it is shocking to think of using a single medication in treatment of HIV, which mutates rapidly.  Current drug regimens typically include two NRTIs and a third medication from a different medication class.  The first protease inhibitor did not become available until 1995.  In 1993, there were already multiple case reports of drug resistant strains of HIV to the only available drug, zidovudine, developing after the patient had been on the medication for six months or longer.

Aside from the vast medical advances we have made in the treatment of HIV, it is also worth reflecting how global society has changed since the CDC first recognized HIV in 1981 to the day my principal retired in 1993 to today.  In the 1980s, a diagnosis of HIV, a virus well known but not well understood, was a death sentence.  The introduction of antiretrovirals provided hope but fear continued to run deep in 1993 and today.

A week ago at the AIDS 2012 conference Hillary Clinton called for an AIDS free generation, an incredibly bold statement that may in fact be feasible if governments, societies, and health-care professionals continue to fight.  I think that making a distinction between an "HIV free generation" and "AIDS free generation" is important to make at this moment.  Hillary's plan outlined in her speech focused primarily on increasing efforts at prevention of new infection, but separating the idea of an AIDS free generation from that of an HIV free one would indicate that improving the quality of care for our HIV positive patients could prevent AIDS and allow all patients with a positive status the right to a long and healthy life.

AIDS, or Aquired Immune Deficiency Syndrome, occurs when the human immunodeficiency virus has destroyed enough of the immune system that it is no longer able to prevent the patient from contracting infections that healthy individuals would not be subject to.  Preventing AIDS would include:

- Test more people: many patients receive a diagnosis of AIDS along with a HIV diagnosis upon initial presentation.  The CDC recommends that all individuals between 13 and 64 years of age receive at least one HIV test in their lifetime and more frequently if they engage in high risk behavior, ie unprotected anal sex and sharing needles.

- Improve follow up.  Many patients receiving a diagnosis of HIV/AIDS never follow up and therefore are unable to receive treatment which would likely result in the progression of their disease to AIDS.

- Get more patients on treatment: medications are expensive but there are a number of assistance programs available.  From a global perspective, many countries reserve treatment for when patients develop AIDS because limited treatment options in certain countries increase the risk of developing resistance or losing control of the epidemic if resistant strains are widespread.  The type of intervention for improvement would depend on the country.

- Get more patients to an undetectable viral load on treatment: This means that the medication is working and the patient is taking it like they are supposed to.  Unfortunately, HIV hides in certain cells and there is no cure for HIV currently, but having an undetectable viral load allows for the immune system to recover.  In a presentation at the conference, it was estimated that about 50% of HIV positive patients (including those not yet tested) had an undetectable viral load versus about 25% of HIV positive patients in the United States.

I was also fortunate enough to attend a profound session moderated by Laurie Garrett, the author of "The Coming Plague", the book that sparked my interest in epidemiology and public health.  She began with a quote from the World Health Organization:

"The social determinants of health are the conditions in which people are born, grow, live, work and age, including the health system.  These circumstances are shaped by the distribution of money, power and resources at global, national and local levels.  The social determinants of health are mostly responsible for health inequities - the unfair and avoidable differences in health status seen within and between countries."  In other words, how do government, health care structure, social norms and culture influence a person's health?

Also on the panel was Dr. Nono Simelela who ran (runs?) the South Africa AIDS counsel and continues to work closely with the current president.  Ms. Garrett set the stage discussing that in a society where 1/3 of the population is HIV positive, people in the society became fatalistic.  They saw HIV as unavoidable with death at its heels, and as a result, this fatalism contributed to increased unemployment and further reduced morale.

Dr. Simelela responded saying that it truly is an epidemic of depravation.  Aside from looking for funding for HIV programs, South Africa analyzed the gains already made and uses allotted funds to not only move forward, but to ensure that the gains made are not lost.  On striving for an AIDS free generation, she discussed the need to get more people involved.  It will not work if it is only government officials changing laws, everyone will need to be an educator.  Patients may spend a few hours with a health care professional per year if they choose to access the health system, but that does not account for the 5000+ hours spent doing everything else.  HIV is an issue that needs to be discussed from different angles.  If people are not talking about it in terms of helping things progress, then little will be gained by society.

I could go on for pages over what I saw at the conference and what was said in this session, but I will end with a quote from a member of that panel, Michaela Clayton, who works in Namibia:

We don't defend human rights because people have HIV, we defend human rights because people have human rights.

References:
http://www.kff.org/hivaids/timeline/hivtimeline.cfm

Erice A et al.  Primary infection with zidovudine-resistant human immunodeficiency virus type-1.  The New England Journal of Medicine 1993; 328:1163-5.

http://www.who.int/social_determinants/en/

Asch DA et al.  Automated hovering in health care - watching over the 5000 hours.  The New England Journal of Medicine 2012; 367(1):1-3.