Table of Contents
A review of:
Live long and prosper with HIV infection and odds are that you will eventually succumb to the diseases of advancing age, which in the prosperous nations of our planet are usually some type of cancer or cardiovascular disease. But, while this may be an expected, even welcome, fate of the older virologically suppressed, HIV-infected patient, there are data suggesting that fatal cancers and cardiovascular disease are also a more immediate consequence of poorly treated HIV infection.
For example, data from the prolific D:A:D study, a collection of prospective cohorts of HIV-infected patients from Europe and North America, demonstrate that among the 20,000 plus participants, malignancies and cardiovascular disease were relatively more common among those patients with lower CD4+ cell counts.1 Additionally, the fatal cancers among the cohort were found largely to malignancies that were not traditionally considered to be AIDS-related, particularly lung cancer.2
Another important data-point in the HIV malignancy plot comes from the SMART study.3 This trial examined a strategy of CD4+ cell count-guided-antiretroviral treatment interruption. The premise of the investigators was that interruptions in highly active antiretroviral therapy (HAART) would provide less exposure to the toxicities of these therapies and, therefore, would yield better clinical outcomes compared to those of patients who were maintained on HIV treatment. As most readers of TheBodyPRO.com know, the study was prematurely terminated last year when excessive mortality and morbidity was observed among those participants who interrupted HIV therapy compared to those who continued on their medications. Prior to being stopped, the trial had lasted a median of about a year and a half.
While much has been made of the cardiovascular, renal and liver events that occurred, the main cause of death during this relatively short-lived study was cancer. Of the 5,472 trial participants enrolled worldwide, 70 participants developed a malignancy during the trial. The study investigators in this paper4 describe these malignancies and identify the factors that were predictive of their development.
As was seen in the D:A:D study, most of the incident cancers that developed during the SMART study were not those traditionally ascribed to HIV infection. Non-AIDS-defining malignancies were reported in 58 participants; in 16 they were fatal. The most common types of non-AIDS-associated cancers were those of the skin (n = 16), lung (n = 8) and prostate (n = 6).
Treatment interruption was associated with AIDS-defining malignancies (i.e., Kaposi's sarcoma, lymphomas) with a hazard ratio of 5.5 (95% confidence interval [CI]: 1.2,25.0; P = .03). The rate of non-AIDS-related cancers was similar between the treatment interruption and continuation study arms. However, the effect of study strategy assignment was strongest in the lowest risk subgroup of participants -- that is, among younger non-smokers, treatment interruption carried a higher risk of the non-AIDS-associated cancers. Notably, the rate of death from any type of cancer was two-fold higher among participants who were interrupting HIV therapy, although this difference was not significant.
The predictors of an AIDS-defining malignancy include a prior history of such a cancer, shorter HIV treatment duration and treatment interruption. In contrast, non-AIDS-defining malignancies were predicted by age, current cigarette smoking (40% of trial participants were smokers), prior non-AIDS-defining cancer and a baseline HIV-RNA level of 400 copies/mL or less (whether this last finding is true or is a fluke is unclear).
The Bottom Line
The higher risk of cancer, especially cancers associated with AIDS, seen in the treatment interruption arm versus the continuous treatment arm provides further evidence against using this CD4+ cell count-guided antiretroviral treatment interruption strategy. The increased risk of AIDS-associated cancers with treatment cessation may be of little surprise given the finding of increased opportunistic infections as seen in this study arm relative to the treatment continuation arm.
However, the trend toward an increased risk of non-AIDS-associated cancers among those with the lowest risk for cancer is concerning and points to a need to reconsider what we consider an "AIDS-related cancer."
Impaired immune function during HIV infection has long been linked to certain cancers -- lymphomas and Kaposi's sarcoma in particular. But, the higher rate of cancers not directly associated with AIDS that was seen during treatment cessation suggests that these malignancies may also arise when immunity falters -- a finding that complements those from a number of other recent studies.5-8
In addition, the finding that these cancers -- such as those of the skin, lung and prostate -- that are not associated with HIV infection were more prevalent than the so-called AIDS-defining malignancies highlights the need for an increased appreciation for the risk of such cancers among HIV-infected patients.
Inspection of the skin, advocating sun protection, smoking cessation, prostate cancer screening, as well as routine cancer screening procedures should be aggressively pursued in men and women living with HIV infection.
Lastly, these findings punctuate the overarching take-home lesson from the SMART study: Stopping HIV therapy and permitting unchecked HIV replication and profound CD4+ cell count depletion is dangerous. These data will also certainly factor into the long running discussion regarding when to initiate HIV therapy. Currently, standard approaches to HIV management tolerate persistent exposure to HIV viremia and progressive CD4+ cell depletion to levels that are 35% of normal prior to the commencement of treatment.
The absence of therapy between the time of infection and the fall in CD4+ cell count below a specified threshold (i.e., 350 cells/uL) has yet to be demonstrated to produce an increased risk for cancers or cardiovascular, liver or renal diseases, but these data from SMART suggest that it may. As efforts to expand HIV screening identify more HIV-infected persons with higher baseline CD4+ cell counts, the advantages and disadvantages of the earlier treatment of HIV infection become less theoretical. Extrapolation from studies like D:A:D and SMART is seductive, but it is clear that what we really need is a well-designed trial to help us find the sweet spot specifying where the benefits of HIV therapies begin to outweigh their risks.
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Death, taxes and middle-age spread: these are the unavoidable certainties of life. That said, the bellies of HIV-infected persons have been the focus of considerable attention over the past decade, particularly as fat wasting of the limbs becomes less of an issue with the demise of stavudine (d4T, Zerit). This has caused more people living with HIV infection to ponder the effect of their HIV therapy on their waist size.
It has been assumed that HIV therapy, particularly protease inhibitors (PIs), increases abdominal adipose volume; however, accumulating data indicate that belly fat generally increases during any effective HIV treatment, including non-PI-based regimens.9-11 Further, the therapies that can reduce limb fat also may reduce subcutaneous fat in the abdomen, complicating the assessment of abdominal fat during HIV therapy.
A major difficulty in determining the role of HIV therapies with regards to changes in body shape over time is the absence of an HIV-uninfected control group. Control subjects can help distinguish the HIV-related factors in body shape change from those that are not related to the virus or its treatment.
In this analysis of the Multicenter AIDS Cohort Study (MACS),12 the waist and limb circumferences of the HIV-infected and HIV-uninfected participants were compared. MACS is a unique, ongoing cohort of men who have sex with men for whom anthropometric measurements, along with other study evaluations, have been performed at six-month intervals since September of 1999.
Of the over 5,600 study participants, 1,053 were available for inclusion in this analysis. The cumulative exposure to different antiretrovirals and antiretroviral drug classes was determined but restricted to the prior three-year period so as to confine nucleoside reverse transcriptase inhibitors (NRTIs) to the HAART era (otherwise exposure to this class of drugs would be impossible to differentiate from the duration of HIV infection, since NRTIs have been available for many years). At baseline, the HIV-uninfected men were older and had a higher body mass index (BMI) as well as waist, arm, hip and thigh circumferences compared to the HIV-infected men.
Among the HIV-infected men, previous exposure to different HIV drug classes had different effects on body measurements. After adjusting for age and CD4+ cell count, NRTI exposure was associated with a significantly greater BMI while PI exposure was not associated with BMI and non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment was linked to a trend toward a higher BMI. Similarly, waist size decreased with cumulative exposure to NRTIs, but PIs and NNRTIs had no effect.
Over time, age was a major factor in BMI and increased waist size in both HIV-infected and HIV-uninfected men. However, waist circumference increased more rapidly among the HIV-infected men. As far as the impact of HIV meds on changes in waist size, individual PIs were not found to be associated with any gains in waist circumference. Zidovudine (AZT, Retrovir) was associated with decreases in arm circumference; stavudine was linked to reduced BMI, hip size and waist size; didanosine (ddI, Videx) was linked with reduced BMI and hip size; and tenofovir (TDF, Viread) was linked with decreased hip size and increased arm width. NNRTIs had no significant effect on anthropometric measurements.
The Bottom Line
The study had three major findings. First, NRTI exposure was linked to decreases in BMI and body circumferences during five years of follow-up. These findings dovetail nicely with clinical trial data demonstrating reductions in adipose tissue during treatment with thymidine analogs. Second, neither PI nor NNRTI exposures were independently associated with changes in anthropometrics at any site. Therefore, this study suggests that other causes for increases in waist circumference during HAART have to be invoked. These data do support the notion of a "return to health" phenomenon in which HIV treatment leads to a generalized increase in weight and fat volume. Lastly, BMI and waist and hip circumferences increased in infected and uninfected men and is largely a function of aging; however, among the HIV-infected participants, waist size increased more rapidly even after adjusting for antiretroviral exposures.
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Is it possible for a serodiscordant heterosexual couple to become pregnant without the uninfected partner acquiring HIV? It's a question that most every HIV-treating clinician has been asked either by a male patient or by the male patient's uninfected female partner. It is easy to underestimate the human desire to procreate and to disregard the desire of HIV-infected men in discordant heterosexual relationships to father a child. However, this primal directive cannot often be quelled simply with a discussion of the finite risk of transmission during unprotected sex (which admittedly is low when the plasma viral load is undetectable13). The lack of available options in the United States to assist such couples can lead to a decision to roll the dice and have unprotected sex.
An option that is often mentioned to these patients is sperm washing -- a process wherein motile spermatozoa are isolated from the semen of an HIV-infected man for use in artificial insemination or some other assisted-reproduction technique. In the United States, the high cost of this procedure and the difficulty of finding clinics that do this for HIV-infected men usually keep this discussion short. In addition, there have been few data regarding the safety vis-à-vis HIV transmission of this procedure.
A report, published in AIDS and presented at the International AIDS Society conference in Sydney from investigators at eight European centers where sperm washing is available, details the outcomes of 533 pregnancies achieved with this method between 1989 and 2003.14 The procedures that were used varied somewhat from center to center, but all involved segregating the spermatozoa from seminal fluid and potentially HIV-infected semen cells followed by the testing of the washed samples for HIV genomes. The assisted-reproduction techniques included intrauterine insemination, in-vitro fertilization and intra-cytoplasmic sperm injection.
A total of 1,036 couples underwent the procedure and in 84% intra-uterine insemination was used. Pregnancy was known to have resulted in 533 (51.4%) women, resulting in 410 deliveries of 463 live births (29 twins and 13 triplets). Six months after the procedure, 967 women had a negative HIV antibody test; the results of the post-procedure testing among the remainder of the women were not known. Therefore, there was no case of female seroconversion following the procedure.
The Bottom Line
These retrospective results from a large number of European couples indicate that sperm washing is effective for procreation. The ability of the procedure to prevent female HIV infection is suggested, but certainly not conclusive given the limitations of this study. For one thing: A significant proportion of women were lost to follow-up or did not have a follow-up HIV test. In addition, the number of couples in the study, although impressive, is too small given the low risk of transmission during a very limited number of exposures.
Nonetheless, these are encouraging findings that will hearten those interested in the procedure. The paper does not describe the cost of the procedure, but in the United States, the price is typically thousands of dollars and is only offered at specialized fertility centers. (There is also the added cost of the assisted-reproduction techniques, which can be between $6,000 to $15,000 for in-vitro fertilization, about $300 for intra-uterine insemination and $1,000 plus for intra-cytoplasmic sperm injection.) In addition to its hefty, if not prohibitive, price tag, couples looking at some of these procedures need to consider a risk that exceeds that of HIV transmission: triplets! Of course, if no fertility drugs are used, there will be little risk of multiple births, but there were 13 sets of triplets seen out of 410 deliveries -- a rate of 3%.
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Approximately 15% to 30% of HIV-infected persons in the United States are coinfected with hepatitis C virus (HCV) and, as a result, liver disease has emerged as a leading cause of morbidity and mortality among such patients. Increasingly, HIV/HCV-coinfected individuals are being offered HCV therapy; however, several clinical trials have demonstrated low rates of sustained virologic response relative to monoinfected patients.15-17 Further, a large proportion of coinfected patients defer therapy -- usually due to an apprehension regarding liver biopsy and/or the toxicity of interferon (Infergen, Intron A, Roferon-A) and ribavirin (Copegus, Rebetol) treatment. In addition, as a consequence of serious mental illness or other conditions, many patients are not candidates for this treatment.
There are data that suggest HIV therapy can attenuate the progression of HCV.18 Other studies indicate that HCV therapy, even when it falls short of a sustained virologic response, can improve hepatic histopathology. Therefore, many clinicians attempt to optimize HIV therapy before they embark on HCV eradication. In particular, in cases of mild liver disease, HCV therapy is often deferred and therapeutic efforts are focused on maximizing immune reconstitution. However, there is a counterbalancing concern regarding the hepatotoxicity of antiretrovirals in patients who can least afford such insults to liver function and that HCV disease can progress while HCV treatment is held back -- risking life-threatening complications (i.e., cirrhosis and hepatocellular carcinoma).
Decision-making here is handicapped because we still have incomplete information regarding the progression rate of HCV in HIV-infected patients. If HCV disease progression is relatively rapid in coinfected patients, the enthusiasm for more immediate HCV therapy increases tremendously -- even in patients with milder disease. Likewise, if rapid progression is more common than currently perceived, patients with minimal liver disease on biopsy who forgo HCV therapy would be urged to be re-biopsied sooner rather than later.
In a straightforward attempt to clarify the pace of HCV disease progression in patients who are also infected with HIV, investigators from Johns Hopkins University in Baltimore, Md., looked retrospectively at the records of 174 coinfected patients who had at least a pair of liver biopsies in the period between 1998 and 2006.19 Patients with cirrhosis on the initial biopsy were excluded from this analysis, as progression was the main endpoint.
The cohort was largely male and African-American. At baseline, more than 60% of the patients were prescribed antiretroviral therapy, and 60% saw their plasma HIV-RNA levels fall to below 400 copies/mL. The median CD4+ cell count was 379 cells/mm3. Almost all (95%) of the patients were infected with HCV genotype 1 and, at initial biopsy, 77% had no or minimal fibrosis seen (i.e., F0, F1).
With a median time between liver biopsies of 2.9 years, 48% of the patients had no evidence of significant fibrosis progression and 22% had minimal progression that was considered not to be significant. However, 24% did experience progression of liver fibrosis, some with marked advancement toward cirrhosis.
In a search for predictors of HCV disease progression, the authors found that CD4+ cell count, HIV-RNA level and HIV therapy were not associated with HCV progression.
Similarly, HCV therapy, prescribed to 21% of the cohort, did not influence fibrosis -- although those receiving HCV treatment had more advanced liver scarring on initial biopsy and only three of these 37 HCV-treated patients achieved a sustained virologic response. Importantly, the extent of fibrosis on first biopsy was not found to be useful in predicting subsequent progression. None of those treated for HCV who experienced fibrosis progression had a sustained virologic response. After multivariable adjustment for HIV-related factors, HCV therapy and transaminase levels, only the serum aspartate aminotransferase (AST) level between biopsies was found to be associated with fibrosis advancement (odds ratio = 3.4, 95% CI: 1.4-7.9).
The Bottom Line
HCV disease progression over an interval of approximately three years was minimal or not evident in 76% of HIV/HCV-coinfected patients. However, a quarter of the patients had substantial advancement to cirrhosis during this period -- a rate of progression that is much higher than observed among HCV-monoinfected cohorts. One positive finding is that antiretroviral treatment did not seem to promote liver injury -- as some have warned -- but, nor was it protective.
What is troubling is that:
In addition, this research group has recently made clear the obstacles to HCV treatment in HIV-infected and HIV-uninfected patients at their institution, including patient refusal to receive treatment and co-morbid conditions that make treatment unadvisable.20
The rapid progression among a sizable minority of HIV/HCV-coinfected patients over a short period of time suggests that clinicians may need to be more aggressive in offering HCV treatment to such patients. The relatively poor performance of HCV therapy in these coinfected patients does not mean this treatment should not be offered to such patients. Even if HCV therapy produces a sustained virologic response in a dismal 20% of coinfected patients, it is worthwhile pursing.
While the poor response to HCV treatment in this population demands the development of better treatment strategies for HCV in the coinfected patient, more robust prospective data have found evidence of the clinical benefits of HCV therapy in coinfected individuals. Also, aggressive treatment programs with multidisciplinary support, including ready access to clinicians and psychological services, have been found to enhance treatment success rates. Further, clinical trials have demonstrated histological improvement even in the absence of a sustained virologic response.16
Importantly, elevated AST (not alanine aminotransferase [ALT]) levels were associated with disease progression in this report and thus patients with higher levels of this enzyme should receive greater scrutiny.
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The avoidance and treatment of antiretroviral resistance are major considerations in the selection of HIV therapy. As such, interpreting the results of genotypic and phenotypic antiretroviral resistance tests has become a requisite skill for the HIV clinician. When first introduced, these resistance assays were fairly straightforward, especially to clinicians accustomed to antibacterial susceptibility testing. However, with the introduction of PIs, resistance testing entered a new, more complicated phase. That's because PI resistance mutations need to accumulate to appreciably reduce viral susceptibility to PIs. Also, defining all the patterns of resistance can be challenging, especially as the potency of these agents improves and viral drug resistance becomes more difficult to cultivate in clinical trials or practice.
Typically, resistance data on new PIs rely on the results of in vitro selection experiments and clinical trials -- where the responses to the drug in patients with differing sets of pre-existing resistance mutations can be assessed. However, neither in vitro selection experiments nor clinical trials may present a complete picture of resistance to a drug. A case in point is with darunavir (TMC114, Prezista), the most recent PI to be approved by the U.S. Food and Drug Administration (FDA).
Data from the phase 2 POWER studies formed the basis of analyses that led to the identification of 11 mutations associated with significantly reduced response to darunavir in vitro and in vivo.21,22 These mutations, listed on a popular pocket card supplied by the maker of darunavir, are V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V.
In the POWER studies, the accumulation of these mutations was linked to a stepwise decline in virologic response rates among study participants such that patients who had one mutation fared less well than those with none, but better than those with two, and so on. There are, however, limitations to this technique for identifying crippling resistance mutations. These include a failure to account for the influence of other antiretrovirals in the regimen on the study outcomes and the potential variability in the relative weight of different mutations on viral replication. For example, it is clear that of the 11 darunavir mutations, some may be more damaging to the antiretroviral effect of the drug than others.
To gauge the prevalence of the gang-of-11 darunavir resistance mutations in a different population than that studied in the phase 2 trials, investigators in California retrospectively examined resistance data from two large clinical cohorts: a population of PI-treated patients receiving care at clinics of the Kaiser-Permanente Medical Care Program-Northern California who had plasma submitted to Stanford University for genotypic resistance testing (n = 1,175) and PI-treated patients described in published studies of the Stanford HIV Drug Resistance Database (n = 2,744).23
As expected, the 11 darunavir resistance mutations were rarely observed (0.06% to 2.3%) among patients who had yet to receive PIs. In contrast, at least one of these mutations was detected in 30% of the Northern California patients and 23% of those included in the Stanford database who had received a PI. Among the Northern California patients, 25% had one or two mutations and 4% had three to six. Less than 1% of the database patients had three or more mutations.
In an analysis of the relationship between prior PI exposure and the number of darunavir resistance mutations for both populations, the number of darunavir resistance mutations was independently and positively associated both with the number of PIs previously received and with having previously received either amprenavir (APV, Agenerase) or fosamprenavir (FPV, Lexiva, Telzir). When the analysis was controlled for the total number of PIs ever received, there was a negative association with having received nelfinavir (NFV, Viracept), in both populations, and with having received atazanavir (ATV, Reyataz) in the clinic population.
Further, these mutations were associated with 17 other mutations of the protease region of the viral genome, suggesting that the collection of 11 mutations reducing susceptibility to darunavir is incomplete. Interestingly, the commonly encountered M46I and L90M PI resistance mutations were found to be markers for the accumulation of darunavir resistance mutations.
The Bottom Line
Darunavir is a potent antiretroviral that has been found to be efficacious in patients with prior PI treatment. As with other new antiretroviral agents, predictions of a response, or lack thereof, have been largely based on data from patients enrolled in clinical studies. In this analysis, a large number of additional mutations were found to be linked with those previously associated with darunavir resistance. The difference between these data and those from the POWER trials may well be explained by differences in the study populations, but suggest that the 11 known mutations, while important, may not be the only significant mutations contributing to drug resistance.
Fortunately, darunavir resistance mutations were rare among patients who were not receiving PIs, but on the other hand a significant minority of PI-experienced patients had at least one of these mutations. Prior treatment with amprenavir or fosamprenavir was also associated with daurnavir resistance mutations, a finding that is not surprising, as darunavir and these drugs are structurally similar.
This report cautions us to check our confidence that the drug resistance patterns derived from clinical trials are sacrosanct or final. This holds not just for darunavir, but for all other antiretrovirals as well. As Richard Haubrich points out in an accompanying editorial, even with this analysis, the darunavir resistance picture is not complete and additional information on the ability of the drug in combination with others and relative to alternative options is required for clinicians to make the best choices for their treatment-experienced patients.24
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Pharmacogenomics is one of those buzz words that (like nanotechnology, gene-therapy and stem cells) conjures up an image of a bright and nearly limitless medical future in which personalized care pushes longevity well beyond the current human shelf life. This is because it was thought that improvements in the understanding of human genetics following the Human Genome Project would lead to a new era in which medication selection and dosing could be tailored to the individual, based on his or her genetically predicted risk of toxicity, effectiveness and metabolism. In practice there has been limited application of host genotype to medical therapeutics.
Recently, however, it has been in the arena of the management of HIV infection where genetics is being used to identify those at risk for drug toxicity: namely the use of HLA-B*5701 testing to screen for the risk of abacavir hypersensitivity.25 Other work among HIV-infected persons has linked polymorphisms in the genes that code for the cytochrome P450 isoenzyme 2B6 with high plasma levels of efavirenz (EFV, Sustiva, Stocrin).26 Specifically, a switch at position 516 from G to T has been associated with an elevated plasma concentration of this NNRTI, as well as the central nervous system adverse effects of the drug.
In this study from Japan,27 the CYP2B6 haplotype of 456 HIV-infected patients who were receiving, or were about to receive, efavirenz was determined. In addition to the previously described CYP2B6 polymorphisms, designated as *6 and found in 18% of the patients, the investigators identified a novel CYP2B6 allele, designated as *26, in 1.3% of the patients. Patients with CYP2B6 *6/*6 and *6/*26 had very high plasma levels of efavirenz.
Next, the investigators took a gutsy approach and reduced the efavirenz dose in 12 patients with high efavirenz levels and undetectable HIV-RNA levels. All 12 patients initially went from 600 mg daily to 400 mg daily of the NNRTI, and seven further reduced their dose to 200 mg daily. In all but one case, the reductions led to declines in efavirenz levels that remained above the threshold of 1,000 ng/mL, which is considered the minimal recommended concentration. One patient experienced a dramatic drop in his efavirenz level from 14,690 ng/mL to 790 ng/mL while on the 400-mg daily dose and had his dose increased back to 600 mg daily. Plasma HIV-RNA levels remained below 50 copies/mL for at least six months in all patients.
Similarly, five patients starting efavirenz who had the CYP2B6 *6/*6 or *6/*26 genotypes were started on 400 mg of the drug. In each case, the viral load was below 50 copies/mL on a pre-switch PI-based regimen. In each case, the levels of efavirenz were considered therapeutic, despite the reduced dose. Two patients eventually had their dose of efavirenz reduced further to 200 mg daily after experiencing dizziness.
The Bottom Line
We are learning that, as with hats and condoms, one size does not fit all when it comes to HIV medications. We have based the dosing of some medications (e.g., stavudine and didanosine) on weight, but there are other less obvious factors that can influence drug exposure, including an individual's ability to eliminate the drug.
The adverse effects of efavirenz are clearly dose-related. There are patients who achieve very high concentrations of the drug -- often due to a genetic tendency to metabolize this medication relatively slowly. This report not only demonstrates that there may be several genes that are associated with a sluggish CYP2B6, but that this knowledge can be used to titrate dosing to achieve targeted levels of the drug, and thereby hopefully reduce the risk of toxicity while preserving effect.
However, the numbers in this pilot study are small and there are few firm conclusions that can be arrived at given this limitation. Further, the declines in efavirenz levels were unpredictable, with some patients experiencing unexpectedly deep declines in drug concentration. However, the results are intriguing and suggest a possible future role for the consideration of pharmacogenomics when using this agent.
This article was provided by TheBodyPRO.com. It is a part of the publication HIV JournalView.