World AIDS Day: Many Gains, Much to Do

Today is World AIDS Day; this is the 25th anniversary of the event. In the past quarter century there have been incredible gains in both HIV prevention and treatment, turning the disease into one that was nearly universally fatal to what is for many a chronic illness with a near-normal life expectancy. On the patient level the gains that have been made are due to antiretroviral drugs ("ART"); access to these life-saving drugs is still a major issue in much of the world, however.

In 2012 there were 2 million new HIV infections and 1.6 million HIV/AIDS related deaths. There are an estimated 35 million people living with HIV globally, with approximately 75% of all new infections occurring in sub-Saharan Africa.

I volunteered providing medical care in a small village in rural Kenya back in 2001. I remember having a conversation with a local health worker about HIV in this particular community and was amazed when she told me the HIV prevalence was over 40%. At the time the people living in the area had essentially no access to life-saving ART and many of the patients I saw had findings consistent with advanced HIV/AIDS and more likely than not are now dead. HIV/AIDS absolutely has devastated many communities in sub-Saharan Africa.

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The picture is not entirely grim, however. The President's Emergency Plan for AIDS Relief (PEPFAR) has led to millions of people in Africa receiving ART, and it is estimated that one million new infections in children have been prevented over the past decade. Many people who once had little to no hope of obtaining ART (such as those living in the community I described above) can now do so.

In the United States it is estimated that 1.1 million people are living with HIV, with 1 in 5 people

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unaware they have the infection. There are an estimated 50,000 new infections per year. There are racial disparities in HIV infection risk that are believed to be due, at least in part, to differences in access to care, poverty and discrimination. Although the incidence of new infections is going down in some subgroups (such as black women), it is increasing in others (such as men who have sex with men).

Much more needs to be done to prevent new infections, identify new infections early and to get patients with HIV into care. Health disparities need to be addressed both in the U.S. and globally. New therapies need to be developed (including a preventive vaccine).

See here for some terrific resources on HIV/AIDS, including more about World AIDS Day.

A Cure for HIV?

Mural in Brussels

Here is a remarkable study by Sáez-Cirión and colleagues that was published this month in PLOS Pathogens. These authors looked at a group of 14 patients with HIV who received treatment early during infection and were able to maintain viral suppression even after coming off HIV medications. 

Historically, there has been controversy over when to start combined antiretroviral therapy (cART) for the treatment of HIV. Traditional arguments against starting cART early in infection included concern over possible long-term medication toxicity, cost and the development of drug-resistance. Arguments for early cART initiation include preserving immune function, reducing host viral reservoirs and limiting chronic immune activation. The study by Sáez-Cirión et al outlines another potential benefit: it is possible early therapy can lead to a "functional" HIV cure. 

Antiretrovirals have literally been life-saving to people living with HIV. Although these drugs suppress viral replication and allow for some amount of immune system recovery, in the vast majority of patients viral rebound and consequent immune system deterioration will occur rapidly once the drugs are removed. There are a small subset of patients (less than 1% of all HIV positive patients) who are, by virtue of gene differences, able to control the HIV virus to levels normally only achieved with cART (these patients are known as "HIV controllers"). 

Sáez-Cirión and colleagues examined a group of 14 patients who were discovered to have HIV very early in their infections and who were provided cART, and later came off cART. These patients behaved very much like "HIV controllers," although they did not have the gene distinctions that allow that group of patients to control HIV. As opposed to the typical scenario (where rebound viremia occurs quickly after cART cessation), these 14 patients demonstrated long-term viral suppression even off cART. These patients were dubbed "post-treatment controllers." The authors estimate that (among patients who are treated early in HIV infection) approximately 15% of patients receiving early HIV therapy may ultimately go on to have long-term viral suppression off cART. 

Although (early) post-treatment control of HIV does not truly represent a cure, for patients who benefit from this phenomenon this may represent a "functional" HIV cure. More study needs to go into this phenomenon and its implications for widespread HIV treatment and policy: will this phenomenon maintain over decades (not just years)? What are the implications of this for vaccine development? Certainly this implies that the immune system can be primed to efficiently control HIV: how can we capitalize on this via vaccination? How can we best identify patients with early HIV infection and get them into care immediately? What about the 85% of HIV positive patients who do not behave like post-treatment controllers?

The article by Sáez-Cirión and colleagues only further tips the scales in favor of early treatment. Antiretroviral drugs have become safer and easier to tolerate over the past decade, and as a result compliance with cART regimens has been easier to maintain. Recommendations for cART initiation have now fully shifted towards early therapy (see the most recent US national HIV treatment guidelines here), with therapy now recommended for all HIV positive patients regardless of immune status. With these new data implying that upwards of 15% of patients may be able to achieve a functional HIV cure with early cART initiation, identifying these patients early and getting them into care is more imperative than ever. 

Time To Stop Smoking: New Study Shows Deadly Effect of Smoking on People with HIV

Here is a study by Helleberg and colleagues looking at smoking-related mortality in HIV patients in Denmark. For people with HIV (in a country where HIV care is organized and antiretroviral therapy is free), smoking was associated with more years of life lost than HIV itself.

These authors looked at 2,921 people with HIV followed in the Danish HIV Cohort Study (from 1995-2010) with 10,642 controls taken from another large population-based cohort.

HIV positive smokers were 5.3 times more likely to die from a non-AIDS related death (cardiovascular disease, cancer, et cetera) than HIV positive non-smokers. AIDS related mortality was higher in HIV positive smokers, as well; they were 4 times more likely to die from an AIDS-related death than HIV positive non-smokers.

The authors estimate that a 35 year old HIV positive smoker has a life expectancy of approximately 63 years; an HIV positive non-smoker has a life expectancy of 78 years. In terms of years of life lost, smoking was associated with 12.3 years of life lost (versus only 5.1 years lost associated with HIV).

Although one could argue that these findings may be difficult to extrapolate to settings outside Denmark (where, again, HIV care is well organized and antiretrovirals are free), these findings are compelling and have implications for managing HIV positive patients worldwide. Although healthcare providers are well aware that smoking causes all sorts of health problems and is associated with increased mortality, this study quantifies the deadly effect of smoking on people living with HIV.

In an era where antiretrovirals have transformed HIV into a chronic illness, we need to re-double our efforts in counseling/ supporting HIV positive patients to stop smoking.

Alabama: Ending Segregation of Inmates with HIV

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Here is a nice New York Times article about the recent Alabama court ruling against the state's policy of segregating inmates with HIV from other inmates. This practice is associated with social isolation, stigmatization, lack of access to certain educational programs and an inability to transfer to prisons closer to families. Inmates are forced to wear arm bands identifying them as being HIV positive, eat alone and are not allowed to work around food; another nice New York Times article about this can be found here.

My friend and colleague Dr. Gonzalo Bearman wrote a very nice blog piece about segregating inmates with HIV back in November that is also worth taking a look at.

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The New York Times article notes that Alabama inmates are not isolated based on having the hepatitis B or C viruses, both of which are more infectious than HIV. All three viruses are transmitted through blood and body fluids. Activities such as having unprotected sex and tattooing (if needles or ink are reused) can lead to acquisition of any of these viruses.

Per the CDC, people who are incarcerated are at increased risk for both acquiring and transmitting HIV. The CDC does not recommend isolating inmates with HIV, however. Rather, the CDC recommends testing inmates for HIV at the time of facility entry and exit, providing educational and treatment programs to inmates who test positive and linking inmates with HIV to care when they are released.

The Alabama court ruling is a definite victory for inmates living with HIV in Alabama. More work needs to be done, however, as this practice of segregation is still in place in South Carolina. Beyond this, prisons and jails should consider adopting practices that will limit infectious disease spread across the board, such as making condoms available.

The Dangers of Recreational HIV Drug Use: "Whoonga"

Here is an interesting NPR story of HIV drugs being used as recreational street drugs. Apparently this is a real problem in South Africa, although the issue has not generated a lot of press to date.

People crush anti-HIV drugs such as efavirenz and or ritonavir and mix these together with illicit substances (such as methamphetamine, opiates or marijuana) and smoke the concoction. In South Africa one such mixture is dubbed "whoonga").

Efavirenz can cause neuropsychiatric side effects (things such as vivid dreams). Ritonavir may boost the effect of other illicit substances.

A 2011 article on whoonga use from the BBC provides a nice overview of this problem in South Africa. A nice commentary piece published in the The Lancet Infectious Diseases on the recreational use of HIV drugs by Grelotti and colleagues (and on which the above NPR story was based) can be found here.

A major problem related to recreational HIV drug use is the emergence of anti-HIV drug resistance. HIV is a viral illness that requires multiple different anti-viral medications used in concert to treat effectively. When the virus is exposed to these drugs intermittently or not in combination drug resistance can emerge rapidly. Smoking "whoonga" essentially does just this: exposes people to intermittent levels of single anti-HIV drugs, thus allowing HIV to develop resistance to that single agent. This has serious consequences for the drug user if they are HIV positive, and to entire communities. If an HIV positive whoonga user develops efavirenz resistance, for instance, they can then pass that resistant virus on to another person.

In resource-limited settings sophisticated drug resistance testing is often not available, further complicating the ability to identify patients who have acquired resistance through recreational HIV drug use, or from contact with a recreational drug user.

The article by Grelotti and colleagues also outlines other potential consequences: diversion of HIV drugs, criminal behavior related to HIV drug diversion that can endanger patients and healthcare providers, et cetera. These authors call for more research into this issue and enhanced screening for recreational HIV drug use by clinicians.

Using HIV Drugs for Staphylococcus aureus Infections?

Staphylococcus aureus (cdc.gov)

Here is an interesting article by Alonzo et al just published in Nature looking at the pore-forming toxin "leukotoxin ED" (LukED) secreted by many Staphylococcus aureus bacteria. Pore-forming toxins create channels in human cells that disrupt cell function and ultimately lead to cell death.

These authors found that a receptor on human T cells, CCR5, which also happens to be a co-receptor for HIV entrance into T cells, is required for LukED activity.

This is interesting in that we already have a drug (maraviroc) used to treat HIV that blocks the CCR5 receptor, thereby disrupting HIV's ability to gain entrance into human T cells. Alonzo et al found that maroviroc disrupted LukED killing of T cells in vitro. These authors used an in vivo model looking at LukED's effect on mice with and without the CCR5 receptor and found mice with the receptor were more likely to die (the implication being LukED cytotoxicity is dependent to a large extent on the CCR5 receptor). 

Not all Staphlococcus aureus isolates harbor the LukeED toxin, and it is not clear if these study findings will translate into real benefits in humans. However, Staphlococcus aureus is a major cause of morbidity and mortality globally, and the above study opens up intriguing new treatment possibilities that may aid in treating these serious infections. More research is warranted. 

HIV: Learning From Stigmatization

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Here is a thoughtful piece from over at PLoS on the stigma associated with various infectious diseases, especially HIV. Despite decades of research and education, discrimination still exists for people living with HIV; Gorman cites examples of people denied employment, of HIV positive inmates being isolated from other inmates and the ban on people with HIV entering the United States that was only lifted in 2009.

She poignantly notes that discrimination leads to false beliefs about disease transmission that in turn drive the stigma associated with disease. She also notes that stigmatization is a not a phenomenon isolated to HIV, but rather has been associated with many infectious diseases throughout history. Stigmas alienate people and undermine disease detection, prevention and treatment efforts.

Gorman calls for research into what drives stigmatization, with a special focus on what we can learn from history. As the emergence of new infectious diseases is a reality of human existence, learning from the stigma associated with HIV and other infectious diseases is critical.

Vitamin D Deficiency: Related to HIV?

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This is an interesting retrospective cohort study published by Sherwood and colleagues looking at vitamin D deficiency (VDD) in patients with and without HIV in a cohort of military beneficiaries; VDD was defined as having a 25-OH vitamin D level < 20 ng/mL and data were collected in the early 2000s. 165  patients with HIV were matched to controls; overall, 85% of patients were male and 61% were black. Patients with HIV were not significantly more likely to have VDD; VDD was associated with black ethnicity regardless of HIV status. Low bone mineral density (BMD) was associated with low exercise, low BMI and with alcohol use, but not with VDD. Low BMD was not associated with tenofovir or other antiretroviral exposure, although there was little tenofovir exposure in this cohort (data primarily collected in early 2000s). 

On the clinical "front lines" it is often difficult to know how aggressively one should manage low vitamin D levels in HIV positive patients: is the concomitant increase in 'pill burden' and its potential negative impact on long-term compliance worth the possible benefit to bone health? If some studies, such as this one, indicate no relationship between bone mineral density and vitamin D levels, are we treating a lab value and not the patient? If VDD and BMD are not definitively linked, why check vitamin D levels at all? Although this study is valuable it does not answer these critical questions; it would be interesting to see this study repeated in the current practice era (e.g., using modern antiretroviral agents according to current practice standards). 

HIV Prevention in Prisons & Jails

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This is a thoughtful PBS piece on HIV surveillance, prevention and treatment comparing 2 systems in Washington, D.C. and Zimbabwe. The article praises recent changes at the D.C. jail that have provided improved HIV testing and treatment resources, as well as condom access and better transitions to outpatient care for prisoners leaving the facility. In contrast, the article cites a Zimbabwe study indicating 49% of prisoners engage in sexual intercourse, however, they are provided no access to condoms. This occurs because homosexuality is illegal in the country. In terms of HIV prevention efforts, not targeting sexual activity in prisons will propagate the epidemic, as 28% of the Zimbabwean inmates in this story were felt to be HIV positive. Although global efforts to both identify and treat HIV infections in prisons and jails are both necessary and laudable, basic efforts to prevent intra-facility HIV transmission (such as providing access to condoms) should also be emphasized.