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Top 10 HIV/AIDS-Related Clinical Developments of 2011

By David Alain Wohl, M.D.

December 1, 2011

Table of Contents

David Wohl, M.D.

David Wohl, M.D.

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As an action-packed year for the HIV/AIDS community draws to a close, TheBody.com takes stock of 2011 in a new series of articles, "2011 HIV/AIDS Year in Review." Read the entire series here.


Introduction

A year can seem like a long time. When our planet was last where it is now relative to the sun, the spewing remnants of the BP Deepwater Horizon rig had just been capped, mid-term elections handed the GOP the keys to the House, and a new-fangled device called the iPad had been in stores for only a few months. In our smaller orbit of HIV-related news, it can be hard to appreciate where we were just a year ago. Below are some of the stories that marked our journey through 2011 and, in some way, changed things from the way they used to be.

1. HPTN 052 to the World: ART = Prevention, Really

The concept of antiretroviral therapy (ART) as prevention is now almost cliché, but it was not long ago that the thought of treating HIV as a means of preventing transmission of the virus could justly be considered avant-garde. Certainly, there were tantalizing data supporting a role for ART in reducing infectiousness. Counting virus in semen and cervical fluid clearly showed that levels of HIV in these compartments fell with the initiation of HIV therapy, reducing inoculum. Observational studies conducted in areas where HIV is endemic found reductions in HIV transmission with the introduction of ART. But, a glass-half-empty skepticism regarding ART as a means to prevent the spread of HIV was common, given concerns about cost, viral resistance and drug toxicity. Then came the HIV Prevention Trials Network (HPTN) study 052.1

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With a Jon-Stewart-worthy "Bam!," the results of this trial snapped us to attention and we all became believers. The trial, long in the planning, was straightforward. Take a large number of couples across the developing world where one partner was HIV positive and the other was not. When the HIV-positive partner's CD4+ cell count was higher than the threshold for ART initiation (greater than 250 cells/µL and below 550 cells/µL), he or she would be randomized to start ART immediately or wait until his or her count dropped below 250 cells/µL (or when clinically indicated). The rate of transmission to the uninfected partner would then be assessed over time. All couples received prevention counseling and ample supplies of condoms. Overall, 1,763 couples were enrolled, more than half from Africa and almost all were heterosexual dyads. Of the HIV-positive participants, half were women and the median CD4+ cell count was just over 400 cells/µL.

At a mean follow-up time of 1.7 years, the study's Data and Safety Monitoring Board (DSMB) determined that the trial results should be made public. There were 39 transmissions to uninfected partners, 28 of which were virologically linked to the HIV-positive partner in the couple. Of these, only one occurred in a couple assigned to immediate ART for the HIV-positive partner. Subsequently, it was found that this one man transmitted HIV very soon after initiating ART. This translates into a relative reduction of 96 percent in the number of linked transmission events with the use of ART for the prevention of HIV to an uninfected partner.

Importantly, the study also addresses the when-to-start-ART question and, in examining clinical outcomes among the HIV-positive participants, found a 41-percent reduction in risk of HIV-related clinical events -- mostly extrapulmonary tuberculosis -- for HIV-positive participants who were assigned to start HIV therapy early. The study follow-up was too short to meaningfully detect differences in survival among HIV-positive participants in each of the study arms.

The Bottom Line

The HPTN 052 study is one of the top HIV stories of the decade, if not ever. This trial demonstrated resoundingly that ART not only lowers the concentration of virus in genital secretions, but that this translates into a reduction in actual infectiousness. Coupled with models describing the potential benefits of the early use of ART on transmission dynamics across a population, this study provides a strong rationale for ART for all HIV-positive persons.

Critics may point to limitations in the study, such as the capping of the entry CD4+ cell count at 550 cells/µL. However, there is little cause to suspect that the effects of ART on transmission would be less at high counts. More important, the HPTN 052 data do not speak to transmission via men having sex with men -- specifically anal sex. Likewise, this was not a study of ART to reduce transmission by needle sharing. These are limitations and extrapolation to anything other than penile-vaginal sexual transmission of HIV would be just that, extrapolation.

Further, there remain concerns about the limitations of ART itself, especially among HIV treatment providers who know well that the ART sword is double-edged. As the prescription of medication is not without its own risks, is it justified to treat an individual with the intention to protect others? This is an important question that could also be asked of other measures undertaken with the benefit of the public health in mind (e.g., vaccinations to provide herd immunity). For many who have drunk the Kool-Aid on ART as prevention, however, the lines between personal and public health are becoming blurred as accumulating data suggest the positive personal health effects of ART even at high CD4+ cell counts (see below).

The ART-as-prevention genie is out of the bottle and as ART continues to improve in terms of tolerability, affordability and convenience, its application for personal and public health is inevitable.

2. The Dawning of the Age of PrEP Leaves Women in the Dark

In the iPrEx trial, published last year, we learned that among highly promiscuous men who have sex with men (MSM), daily oral Truvada (tenofovir/FTC) reduced their risk of acquisition of HIV by 44 percent -- a modest effect, but encouraging to many who look to ART as a chemical condom for those not interested in the latex kind.2 However, before we all cheer the advent of yet another little blue pill to make sex better, it would be nice to see if it also works in women, who often also have sex with men.

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The FEM-PrEP study, designed to do just that, enrolled 1,951 women who were at high risk of acquiring HIV and who lived in Kenya, Tanzania or South Africa.3 All were randomized to daily oral Truvada or placebo. In April, a DSMB committee advised the investigators to close the study, as there was little chance that the trial would be able to demonstrate an effect of the intervention on transmission. Details regarding the outcomes are not fully available, but we do know that enrollment was hampered by a high rate (~20 percent) of HIV among women being screened for the study. The rate of new HIV infections among trial participants was 5 percent per year and, among the 56 new HIV infections that occurred, an equal number were in those participants assigned to Truvada as those assigned to a placebo.

On the heels of this announcement came a similar release from the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study.3 This is a placebo-controlled study comparing daily use of oral Truvada versus oral Viread (tenofovir) alone versus a Viread-based vaginal gel in preventing male-to-female HIV transmission in South Africa, Uganda and Zimbabwe. In September, an independent monitoring determined that the oral Viread arm would be highly unlikely to be distinguishable from placebo and should be stopped. The other study arms continued until November when the safety board then determined that the Viread gel arm should also be stopped for reasons of futility. This leaves the Truvada arm, which will be observed.

The Bottom Line

We do not know for certain how well oral Truvada works as pre-exposure prophylaxis (PrEP) for women. Many suspect that poor adherence explains the lack of efficacy of Truvada in FEM-PrEP, and perhaps the Viread gel in VOICE. In the Partners PrEP trial, a different study that enrolled over 4,700 HIV-discordant heterosexual couples, oral daily Truvada provided a 73-percent-reduced risk of transmission (62 percent for women and 83 percent for men) compared to placebo and adherence was reportedly over 95 percent.4 Similarly, the TDF2 study, conducted in Botswana, found a 63-percent reduction in HIV acquisition among 1,219 men and women randomized to oral Truvada versus placebo.5 Again, in this study, adherence was measured to be high at about 84 percent. The study was not powered to detect differences in efficacy by gender. As far as the efficacy of the Viread gel, the CAPRISA study conducted in South Africa showed decent efficacy that, not surprisingly, was dependent on adherence.

While adherence may explain differences in study results, it may also provide a view of what the real-world experience will be when HIV-uninfected persons use ART to prevent their own infection. Unless interventions that blow away those being used to support ART adherence among HIV-positive patients can be developed, PrEP may turn out to be effective, but difficult to translate into practice.

There may also be biological explanations for gender differences in the efficacy of oral PrEP. Vaginas and anuses are just plain different and the ways in which drugs reach and remain active in the tissues of these orifices are not the same.

So for now, we are left with study results that are mixed when it comes to women and PrEP. Additional research will provide more data points. We will certainly learn more about the tissue activity of antiretrovirals in women and, further down the line, there will also be data looking at other agents, such as Selzentry (maraviroc, Celsentri), as PrEP in both men and women, as well as ART gels at different time schedules. Until then, we wait.

3. It's the Virus, Stupid: Viremia Copy-Years

That HIV is bad for you is indisputable. But how bad is the virus itself? What harm does it do as it endlessly replicates? Until recently, we were generally comfortable allowing HIV to go unmolested among patients with high CD4+ cell counts. Now, as we begin to appreciate the axis of evil among viremia, immune activation and inflammation, and we move toward expanding the HIV-treatment net, it is reasonable to ask how harmful it is to have circulating virus over time.

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Researchers from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS), a network of clinical sites across the U.S., have devised an interesting method of examining the viral load not at a single, cross-sectional time point, but over time to arrive at a cumulative burden of HIV.7 Called viremia copy-years, this technique provides an area-under-the-curve of HIV exposure that can be examined against a variety of outcomes. The concept is similar to that of pack-years of cigarette smoking.

In this paper, data from 2,027 patients initiating ART from 2000 to 2008 were used to calculate viremia copy-years and then evaluate the association between this and mortality. The median CD4+ cell count at treatment initiation was just over 200 cells/µL and, after a median follow-up of 2.7 years, patients each contributed a median of eight viral load determinations. Most (81 percent) were virologically suppressed by six months after ART was started, but 4 percent of the cohort had died (after a median of two years).

Median viremia copy-years was 5.3 log10 copy X years/mL. The unadjusted hazard ratio (HR) for log10 viremia copy X years/mL was 1.81 (95% CI: 1.51-2.18), indicating that for each log10 increase in viremia copy-years, the hazard of death increased nearly two-fold. In adjusted and weighted analyses, viremia copy-years was independently associated with mortality (HR 1.65; 95% CI: 1.32, 2.06). In analyses that included demographic and clinical covariates, the cross-sectional viral load measures were no longer associated with mortality. In addition to viremia copy-years, having a lower most recent CD4+ cell count and older age were each also independently associated with an increased mortality risk.

The Bottom Line

The cross-sectional viral load is useful in a clinical setting, but it fails to capture the longitudinal exposure of the patient to HIV -- plus, it is so 2010. Instead, viremia copy-years provided a Cassandra-like power to determine the risk of all-cause mortality in this large sample of patients initiating therapy. An independent 44-percent increase in mortality risk was observed per 1 unit increase in log10 copy X year/mL of cumulative viral load burden. Thus, viremia copy-year was up there with age (life's greatest risk factor for death) and recent low CD4+ cell count as a harbinger of doom.

Importantly, greater exposure to HIV over time was predictive of death independent of the most recent CD4+ cell count. This supports the idea that viremia is harmful even when CD4+ cell counts have not been decimated. Further, this work dovetails nicely with observational cohort data, including a pooled analysis of over 40,000 patients from Europe and North America who were not receiving ART and had at least a single CD4+ cell count above 350 cells/µL, that found higher rates of death even at higher CD4+ cell counts compared to the general public.7

It has been assumed that the excess risk of illness and death at higher CD4+ cell counts comes at the hands of immune activation and the inflammatory responses it provokes. In the CNICS study, markers of inflammation and immune activation were not included as this was a retrospective analysis, but such data would help close the loop of association between viremia and death.

Nevertheless, these findings provide important additional evidence of the deleterious effects of ongoing viremia on health and have introduced us to a new concept of continued viral replication.

4. Race and Gender ART Outcome Differences: A5202

The literature on racial and gender differences in the clinical outcomes of those treated with ART poses more questions than answers. It is a complicated science and when looking at race, the data must be evaluated in the context of an overall increased risk for poorer outcomes among African Americans than for whites in the general population. Since the introduction of potent combination ART, mortality rates among HIV-positive persons have declined substantially for all, but the benefits have been uneven with African Americans, especially African-American women, seeing smaller gains in survival.

Race can be a marker for other factors that influence well-being, including access to health care, insurance availability, and the stress that has been associated with being black in America, among others. According to one important model, much of the racial disparity in HIV outcomes can be explained by a later start of ART and an increased rate of treatment discontinuation for blacks compared to whites.8

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An analysis of data from the Women's Interagency HIV Study (WIHS) and the all-male Multicenter AIDS Cohort Study (MACS) found that HIV-RNA levels were 30 percent to 50 percent higher in men than in women, but that women experienced disease progression at lower viral loads.9 However, although most of the women in WIHS are non-white and the majority of the men in MACS are white, the role of race was not examined.

The AIDS Clinical Trials Group (ACTG) study A5202 provides an opportunity to address gender and race disparities on the (more) level playing field of a clinical trial.10 A5202 was a four-arm study looking at the efficacy and safety of Truvada versus Epzicom (abacavir/3TC, Kivexa) in combination with either Sustiva (efavirenz, Stocrin) or Norvir (ritonavir)-boosted Reyataz (atazanavir).

There were 1,857 participants enrolled from sites across the U.S. Of these, 17 percent were women, 40 percent white non-Hispanic, 33 percent black non-Hispanic, and 23 percent Hispanic. As predicted by the model mentioned above, blacks did have a lower baseline CD4+ cell count (24 percent versus 13 percent with less than 50 cells/µL, P < .001), although viral load was also lower for blacks (63 percent versus 46 percent with less than 50,000 copies/mL, P < .001) than whites (perhaps because a greater proportion of black participants were women).

During the study, black participants had a higher risk of virologic failure compared to whites and Hispanics (for whom outcomes were similar); however, there was no significant difference in the time to failure between men and women. It was when looking at the specific regimens that major differences in virologic outcomes became apparent.

Women assigned to Reyataz+Norvir had a higher risk for virologic failure with either nucleoside reverse transcriptase inhibitor (NRTI) backbone than women assigned to Sustiva and compared to men assigned Reyataz+Norvir. Interestingly, comparing Reyataz+Norvir to Sustiva, there was no significant difference in time to safety/tolerability events by gender.

Women did have an increased risk of moderate to severe toxicity with Epzicom compared to men receiving these NRTIs. Blacks, but not Hispanics, had an increased risk of a tolerability endpoint with either Reyataz+Norvir or Sustiva compared to whites (1.37 [1.44 to 1.65] P = .0007).

Self-reported adherence at two months was high overall (92 percent with 100 percent adherence) and did not differ significantly by gender. However, blacks, but not Hispanics, were more likely to report less than 100 percent adherence than whites, with the percentage reporting less than 100 percent adherence about double for blacks compared to whites.

The Bottom Line

This large, randomized trial presents fascinating data on differences in outcomes with commonly used ART regimens by gender and race. As seen before, blacks did not fare as well, possibly related to suboptimal adherence and greater rates of overall medication intolerance. For women, the key finding was that Reyataz+Norvir was not as well tolerated as Sustiva. There is speculation that women do not tolerate Norvir as well as men. In fact, in the ACTG study A5175, where Reyataz without Norvir was studied, women were not found to have higher rates of treatment failure compared to men and there were no gender differences in tolerability.

These data raise an important question regarding the need to tailor therapy based on patient characteristics. If women do indeed tend to have a greater intolerance to Norvir, then effective regimens that spare this protease inhibitor may be preferred. Studies have demonstrated the efficacy of unboosted Reyataz, but these have not provided much traction for such an approach in clinical practice -- likely due to the sense of security Norvir boosting provides against drug resistance and the need to use Epzicom instead of Truvada given the effect of Viread on Reyataz levels. If Norvir is not women-friendly, this strategy will need to be reconsidered.

The lower adherence rates and greater intolerance to the protease inhibitor and non-nucleoside among black participants in this trial also require greater scrutiny. Much of the adherence intervention literature is now dated and new ways of thinking are needed to support the care of people living with HIV today. African Americans, especially young black MSM, are at the greatest risk for HIV in the U.S. and face challenges to successful management of HIV that are unique. All the evidence points to poverty, discrimination, and other structural mega-factors as having a tremendous role in the chance for success -- problems that cannot be countered solely with a series of counseling sessions, electronic reminders or co-formulated medications. If anything, the A5202 data make it clear that there are differences in ART response by race and gender. The challenge now is what to do about it.

5. No Go Isentress+Prezista/Norvir

Cowboys and cowgirls, you know who you are. You are the early adapters; the ones who see a presentation on a 50-patient, single-armed study from France of a novel ART combo and can't wait to try it in clinic when you get back home. You extrapolate and eschew evidence-based-minded colleagues as stodgy. Often, you are considered a thought leader. Usually, the data catches up and vindicates your prescience. Except sometimes it does not.

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A year or so ago, the NRTI-sparing regimens had a bit of a renaissance with the advent of the integrase inhibitor Isentress (raltegravir). The bold among us started to use imaginative pairings of Isentress with boosted protease inhibitors in an effort to relieve us of the NRTIs and provide an attractive option for those failing Atripla (efavirenz/tenofovir/FTC). The inklings were there. In ACTG study A5142, the NRTI-sparing regimen of Kaletra (lopinavir/ritonavir) plus Sustiva produced a virologic response that was no different than two NRTIs plus Sustiva among treatment-naive patients.11 The major limitation of that two-drug regimen was tolerability, not efficacy.

So, all we needed to do was a study to prove us right, and A5262 was to be it. In this single-arm study, 112 ART-naive patients were treated with Prezista (darunavir, TMC114) plus Norvir (800 mg/100 mg daily) plus Isentress (400 mg twice daily).12 The single-arm design was intended as an efficient and quick way to study this novel combination. Without a comparator arm, the study was designed to look at response relative to the results of other treatment-naive studies. The acceptable virologic failure rate was estimated using the week 24 virologic failure rates of the Sustiva plus two-NRTI arm of A5142 (22 percent); the Sustiva plus two-NRTI arm of ACTG A5095 (17 percent); and the Truvada plus Isentress arm in several trials (10 percent to 15 percent). It was pre-specified that the study regimen would be considered satisfactory if the upper bound of the confidence interval for cumulative virologic failure at week 24 was less than 35 percent.

When the dust settled, 17 (16 percent) of the participants experienced virologic failure (95% CI 10-24) by week 24 and 26 percent (95% CI 19-36) by week 48 in an intent-to-treat analysis. Eleven participants had failed to suppress viremia and six rebounded. An additional 11 participants experienced virologic failure after week 24, for a total of 28 virologic failures during the study. In the intent-to-treat analysis (missing and off study without virologic failure were ignored), the viral load was less than 50 copies/mL in 79 percent (95% CI 70-86) of participants at week 24 and less than 50 copies/mL in 71 percent (95% CI 61-79) of participants at week 48. Interestingly, 21 of the 28 who failed had baseline viral load levels of greater than 100,000 copies/mL. After adjusting for age and sex, virologic failure was associated with a baseline viral load of more than 100,000 copies/mL and a lower CD4+ cell count. Five participants had integrase mutations during virologic failure and all had a baseline viral load of more than 100,000 copies/mL. No new protease inhibitor resistance was detected among those failing. Overall, the regimen was well tolerated.

The Bottom Line

The combination of Prezista+Norvir+Isentress did not bomb, but the results were nonetheless disappointing. Using a modified intent-to-treat analysis where missing and off treatment were considered to be failure, only 61 percent of participants had a viral load below 50 copies/mL at week 48 -- a response rate that was much lower than that seen with standard initial regimens and the A5142 NRTI-sparing combination.

The reason for the lackluster response of the study treatment is unclear. Self-reported adherence was not different between those who did and did not experience virologic failure. However, a lower plasma level of Prezista or Isentress was associated with failure, possibly indicating unreported suboptimal adherence. Further, in another study, the PROGRESS trial, Isentress+Kaletra was found to provide similar virologic responses as Kaletra+Truvada. A potentially important difference between that and the ACTG study was an overall lower baseline viral load in the PROGRESS trial.13

It is the finding that a high baseline viral load was strongly associated with virologic failure that suggests an issue with potency. It is never a good sign when a regimen falls flat among those with higher viral loads. Some have speculated that effective ART regimens require a drug active prior to the integration step of the viral life cycle, thus the better success of an NNRTI plus protease inhibitor combination. Regardless of the cause for the higher-than-expected rate of virologic failure, this regimen should be used cautiously, especially in those with higher viral loads.

The pull to go beyond the evidence is strong in the field of HIV management. Patients burn through regimens faster than clinical trials can provide data to guide the next steps. With over 25 drugs on our palette, we concoct mixes that should work based on what we know and believe. This is what makes HIV care exciting and, to some extent, creative. The story of A5262 shows us, though, that we can be wrong and that faith may be unwarranted. Sometimes, even the best cowboys and cowgirls lose, only to fight another day.

6. No Go Isentress QD

For once-a-day Isentress, the story is less one of audacity than of hope. Twice-a-day regimens are now considered by most providers and many patients to be one dose too many, and there was a real desire to see otherwise-user-friendly Isentress join the other preferred ranks by becoming once a day. Pharmacologic data from Merck, the maker of the drug, suggested that the business end of Isentress was intracellular and that plasma levels were not the best indicator of what this integrase inhibitor could do. Therefore, it was with confidence that the QDMRK trial was launched.14

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In this placebo-controlled study, 775 treatment-naive patients were randomized to Isentress once a day versus twice a day, both in combination with Truvada. At baseline, 39 percent of the treated patients had viral loads of more than 100,000 copies/mL and 24 percent had CD4+ cell counts of fewer than 200 cells/µL. Of the once-daily group, 83 percent had virological response, versus 89 percent in the twice-daily group (difference: -5.7 percent, 95% CI: -10.7 to -0.83; P = .044). Therefore, once-daily dosing of Isentress was inferior to twice-daily dosing of the drug. The difference in responses was even greater among those with baseline viral loads over 100,000 copies/mL: 74 percent versus 84 percent in the once-daily and twice-daily arms, respectively (difference: -9.9 percent, 95% CI -19 to -0.8). A similar splay was seen in those with CD4+ cell counts below 200 cells/µL at entry.

Of the 53 recipients of once-daily Isentress with virological failure, 22 (42 percent) never responded and 31 (58 percent) had viral rebound. Of the 35 recipients of twice-daily Isentress with virological failure, 14 (40 percent) never responded and 21 (60 percent) had viral rebound. Integrase mutations were more commonly seen in the once-daily arm, as was resistance to Emtriva (emtricitabine, FTC).

Serious adverse events were reported in 7 percent of the once-daily recipients and 10 percent of the twice-daily recipients, and adverse events leading to discontinuation occurred in four patients (1 percent) in each group.

The Bottom Line

If wishing alone had mattered, the results of this study would have been different. But it was not to be. Again, it is not that once-a-day Isentress was awful. Rather, it was not as good as twice-a-day dosing of the drug. For those with baseline viral loads of over 100,000 copies/mL or CD4+ cell counts below 200 cells/µL, there was a more substantial difference, which would preclude most use of once-daily Isentress in such patients.

7. New HCV Therapies

Hepatitis C (HCV) therapeutics is entering a revolution akin to that seen with the first protease inhibitors for the treatment of HIV infection. Two new, oral HCV protease inhibitors, Incivek (telaprevir) and Victrelis (boceprevir), were approved for the treatment of those mono-infected with HCV genotype 1. The approval of these so-called "direct-acting antivirals" (DAAs) has created a renewed awareness about HCV and has raised the hopes of those infected -- including patients who harbor both HIV and HCV -- that the days of interferon are numbered.

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The addition of either of these new HCV drugs to a standard regimen of interferon and ribavirin (brand names: Copegus, Rebetol, RibaTab, Ribasphere) almost doubles the rate of HCV cure in the mono-infected, but there are few data regarding their use in coinfected patients. It is known that patients with HIV and HCV do not respond as well to standard HCV therapy. Further, there is the potential for significant drug-drug interactions between ART and both Incivek and Victrelis.

Mark Sulkowski from Johns Hopkins and colleagues conducted the most important study to date that addresses the use of a DAA for coinfected persons.15 One hundred HCV treatment-naive patients with HIV coinfection were randomized 2:1 to Victrelis 800 mg three times a day plus standard therapy of 1.5 mcg/kg/week pegylated interferon alfa-2b (brand name: PEG-Intron) and 600-1,400 mg/day weight-adjusted ribavirin versus standard therapy alone.

For those in the experimental arm, Victrelis was added to pegylated interferon and ribavirin after a four-week lead-in for 48 total weeks of therapy. Those with detectable HCV RNA and less than a 2-log10 decline in HCV viral load at week 12, or detectable HCV RNA at week 24, stopped treatment given data suggesting very poor likelihood of response.

The participants were mostly male and white, and two thirds had genotype 1a. All were receiving ART with HIV-RNA levels less than 50 copies/mL and CD4+ cell counts of at least 200 cells/µL. ART was limited to two modern-era NRTIs plus a boosted protease inhibitor, given previous data demonstrating a reduction in Victrelis levels when co-administered with Sustiva.

At 24 weeks of overall therapy, over 70 percent of those in the Victrelis arm had undetectable HCV-RNA levels compared to 34 percent of those assigned standard therapy alone. Rates of complete early virological response (cEVR) at week 12 were 59 percent versus 26 percent, respectively. Further, Victrelis was generally well-tolerated, although those assigned this drug had more fever, anorexia, vomiting, headache, altered taste and neutropenia. Overall, 14 percent in the Victrelis arm and 9 percent in the standard-therapy-alone arm discontinued therapy due to adverse events.

The Bottom Line

New HCV therapies are a big deal for the millions of people infected with HCV, as well as for the third who are coinfected with HIV. Low response rates combined with the agony of interferon/ribavirin have prevented many with and without HIV from attempting HCV treatment, but with a greater chance for cure, many are more willing to give HCV treatment a try.

Before taking such a plunge, people with HIV infection and their providers need additional data on the safety and efficacy of both Victrelis and Incivek in coinfected patients. This small, but impressive, study provides reassurance. Another, even smaller, study of Incivek found similarly high response rates in coinfected participants.16

There are still questions about drug interactions that need to be worked out and there are ongoing discussions regarding which patients are most appropriate to treat now versus later. Most every pharmaceutical company has an HCV drug or two in its pipeline and some of these may even be able to be combined into an interferon-free regimen. Therefore, with the possibility of newer, potentially more potent and better-tolerated therapies in the offing and the possibility of cross-resistance across HCV protease inhibitors, use of these first DAAs should be judicious. For those patients with less inflammation and fibrosis on liver biopsy, waiting for the next generation of HCV drugs seems prudent. Those with more advanced evidence of liver disease may not have the luxury of waiting two or more years for better therapies to arrive and for these patients Victrelis and Incivek make more sense.

There are a number of studies of both drugs starting up in HIV/HCV-positive patients, including a new ACTG study of Victrelis. This is an exciting time for HCV therapy and, after having pitifully few options to offer our patients, it will be gratifying to be able to cure more of our patients of HCV.

8. New One Pill Once a Day

The release of co-formulated Atripla was a major milestone for the treatment of HIV infection. Not only was the combination of ART that is included in the tablet unsurpassed in efficacy, but the psychological impact of being able to treat this infection with one pill a day was substantially positive for patients.

Since then, other potent, once-a-day regimens have come on the scene. However, none are one pill, one bottle and one copay. Enter the fixed-dose combination of Complera (rilpivirine/tenofovir/FTC), released this year. Edurant (rilpivirine) is a new NNRTI that cut its teeth in the ECHO and THRIVE trials of treatment-naive patients. Originally available as a standalone ART, the co-formulation with Viread and Emtriva provides another one-pill-a-day option for patients.

The Bottom Line

Co-formulation improves adherence and reduces costs for those with insurance copays. The new, fixed-dose formulation was intended to be a new-and-improved version of the first one-pill-a-day, Sustiva-containing tablet. However, the ECHO trial comparing Edurant with Sustiva found higher rates of virologic failure among Edurant-assigned patients with a baseline viral load greater than 100,000 copies/mL. Further, among those failing Edurant, there was a significant risk for the development of resistance mutations that precluded the use of the second-generation non-nuke, Intelence (etravirine, TMC125).

Therefore, although better tolerated than Sustiva and able to be taken during the day, rather than before bed, Edurant will continue to play second fiddle to its older classmate. Still, for some patients, such as those with lower viral loads, who like to eat and are not on a proton pump inhibitor, this is a fine option.

Other one-pill-a-day ART regimens are in the offing and we should not take for granted how far we have come in providing HIV therapy that marries potency with convenience. If the advent of single-pill ART has not adjusted clinicians' thinking of HIV as a deadly foe, it certainly has helped many patients to accept that their infection is manageable and something they can live with.

9. Rising Rates of HIV Among BMSM

Those of us who work in clinics that see new HIV infections know it, but it seems like most everyone else remains oblivious to the surge of HIV among young black men who have sex with men (BMSM). In 2006, when the U.S. Centers for Disease Control and Prevention (CDC) released a new estimate of 56,000 annual new HIV infections, it also reported that over 50 percent of the cases were in MSM. What was lost was just who these men were. In an update to that estimate that includes data up to 2009 and employs improved methods to account for missing data, the CDC highlights the leading edge of the epidemic in the U.S. is BMSM.

The annual incidence of HIV in 2009 is estimated at 48,100 (95% CI: 42,200-54,000); the HIV incidence from 2006-2009 was stable. However, in 2009, MSM accounted for 61 percent of new infections and there was a 21-percent increase (P = .017) in HIV incidence for people aged 13-29, driven by a 34-percent increase in MSM. Further, there was a 48-percent increase among young BMSM (P = .001). In fact, among people aged 13-29, only MSM experienced significant increases in incidence, and among 13- to 29-year-old MSM incidence increased significantly among young BMSM. In 2009, heterosexual contact accounted for 27 percent of new cases, injection drug use (IDU) for 9 percent, and MSM/IDU for 3 percent.

The Bottom Line

The domestic HIV epidemic has locked young BMSM in its sights and pulled the trigger. Frustratingly, the reasons that young BMSM are at such a heightened risk for HIV acquisition remain unclear. High rates of HIV in African-American communities, the use of the Internet and social networking to facilitate risky hook ups, concurrent sexually transmitted infections, homophobia, and other factors have been invoked to explain this epidemic within the epidemic.

Increased access and uptake of HIV testing have become a priority in many urban areas and are the centerpiece of the CDC's "Testing Makes Us Stronger" campaign. This is one of several national and local initiatives described in the White House's National AIDS Policy (see www.whitehouse.gov/blog/2011/09/27/addressing-hiv-epidemic-among-gay-and-bisexual-men) that include enhanced testing and counseling aimed at young African Americans.

One can only hope that these and other initiatives can survive the budget standoff sequestration process and other deficit-reduction activities. But, demonstration projects and CDC- and National-Institutes-of-Health-funded studies alone will not make a difference. Knowledge has to be put into practice in order to be powerful. Even now, with what we know, more can be done. As Dr. Kevin Fenton, Director of the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention at the CDC, pleads:

Today, right now, we desperately need new champions and leaders from the gay community and from all communities where MSM are heavily affected to take this information and these promising breakthroughs and help to nurture a movement that not only promotes awareness of the HIV epidemic and its toll on gay and bisexual men but access to education, prevention, and care to make full use of all of the tools we have at hand currently. The gay community's leadership once drove the nation to act against AIDS -- that same energy and commitment is needed today. We cannot allow the health and the lives of gay and bisexual men to be lost to a preventable disease.

Amen.

10. What Can We Expect After Test and Treat?

We have shifted into test-and-treat mode to rein in HIV (see above). The idea is that finding those with HIV will then allow for counseling and the prescription of ART, which in turn will reduce the risk of secondary HIV transmission. However, there are a number of Achilles' heels along the sequences of events from positive test to durably suppressed viral replication. So, while test and treat has in itself become a viral concept, the good things that are to follow are assumed, rather than assured. After all the testing and treating is done, what really happens?

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In an interesting amalgam of a paper that includes literature review, data mining and modeling, Edward Gardner and colleagues look at engagement in HIV care, how well we do and how we can do better at keeping viral loads undetectable.18 Critical to the test-and-treat strategy's effectiveness is the engagement of HIV-positive persons in care long term. Only with continued monitoring of ART and the reinforcement that accompanies clinic attendance can we expect viremia to be suppressed.

Using data from disparate sources, the investigators derive an estimate of the proportion of HIV-positive people in the U.S. with an undetectable level of plasma HIV viral load -- a sorry 19 percent. As Joep Lange in an accompanying editorial states, this is a shocking figure given we are 15 years into the era of highly active antiretroviral therapy, the last four of which saw a well-tolerated, one-pill, once-daily treatment option.

In what may become an enduring figure, the paper illustrates the lost opportunities in graphic form.

Failure to diagnose, failure to link to care, failure to retain in care, failure to provide ART, and failure to take ART all conspire to whittle down the number achieving suppression.

Sobering are the simulations that the investigators perform that suggest it will not be easy to increase the proportion of HIV-positive people in the U.S. that have undetectable HIV-RNA levels. Simply increasing the proportion of infected individuals who are aware they are HIV positive to 90 percent would increase the rate of being undetectable to only 22 percent. Engaging in care 90 percent of those currently aware they are HIV positive raises the figure to 34 percent. Assuming 90 percent of HIV-positive patients receive ART has minimal effect; similarly assuming 90 percent of patients on ART are undetectable has little impact. It is only by combining interventions so that 90 percent of HIV-positive individuals know their diagnosis, 90 percent of them engage in HIV care, 90 percent receive ART, and 90 percent achieve an undetectable viral load that we can expect a much more reasonable 65 percent of infected persons to have an undetectable HIV viral load.

The Bottom Line

The derived estimates and simulations used in this paper are somewhat simplistic, but they are likely not far off the mark. A similar analysis, published by the CDC in the Morbidity and Mortality Weekly Report (MMWR) for World AIDS Day, estimates that 28 percent of those infected are undetectable. Either way, these data indicate that testing and treating alone are not the complete answer to the question of how do we stop HIV in its tracks. We are armed with potent HIV therapies and we have a comprehensive health care apparatus for getting most HIV-positive people ART. Yet, we have not fully realized the potential of either.

Expanded testing makes sense on many levels. New guideline recommendations that expand ART to those with higher CD4+ cell counts and growing awareness of the public health benefits of ART are likely to boost the numbers of people with HIV who are prescribed ART (provided AIDS Drug Assistance Programs can continue to provide ART for the middle class and the poor). Therapies are becoming easier to take and that can help with adherence. Therefore, the stars are aligned for our getting better control of HIV on a population level and for the test-and-treat story to have a happy ending.

Conclusion

It was a busy year in which the outlines of the challenges we face in finally containing the HIV epidemic became brighter. At the same time, we also saw that creative use of our therapies can make a huge impact in both treatment and prevention. The limitations of our biologicals -- be they for treating HIV, preventing new infections or, even, curing HCV -- rely on patient buy-in and support. Changing behavior is hard (if it was easy, we would be spending millions on condoms, rather than Viread). But, change is possible if we understand why people act the way they do and then use this information to creatively and constructively support health. The obstacles are huge and it may take a revolution, but then don't you want to change the world?


References

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