What We’re Reading

Each issue of the Topics, Trends & Updates email includes a summary of a recently published journal article, written by Christopher Hoffmann, MD, MPH, Principal Investigator of the HIV Clinical Guidelines Program. Dr. Hoffmann is an assistant professor of medicine at the Johns Hopkins University School of Medicine, Division of Infectious Diseases. 

Articles are chosen to highlight topics that are directly relevant to clinical practice in the U.S. and that are not already widely summarized by other authors. 

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Vitamin D Deficiency Associated with Statin-Induced Muscle Toxicity in Patients Living with HIV (3/17)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University School of Medicine

A recently published study supports the association between statin-related myalgia and vitamin D deficiency among people treated with antiretroviral (ARV) agents, with an impressive effect size of 2.3 [Calza L, et al. AIDS 2017 Mar 13;31(5)].

Several antiretroviral (ARV) agents are associated with hypercholesterolemia. In addition, some ARVs, and a pro-inflammatory state caused by HIV itself, can increase the risk of cardiovascular disease (CVD). For these reasons, both hypercholesterolemia and CVD appear to be increased among people living with HIV. Statins play an important role in managing hypercholesterolemia and in reducing the risk of CVD, thereby reducing mortality, among patients living with HIV. The American College of Cardiology and the American Heart Association recommend statins for all individuals at high risk of cardiovascular disease [Stone NJ, et al. J Am Coll Cardiol. 2014 Jul 63(25 Pt B)]. Whether a role for statins exists among people living with HIV who are at low to moderate risk of cardiovascular disease is being evaluated in the REPRIEVE study.

Adherence to statin treatment can be compromised by muscle toxicity. In the general population, between 10% and 25% of individuals taking statins report having myalgia, and many discontinue the therapy as a result. Further, vitamin D deficiency has been associated with statin-induced myalgia in the general population. Given the frequency of vitamin D deficiency among people living with HIV (70%-84%), Calza and colleagues [AIDS 2017 Mar 13;31(5)] performed a retrospective analysis in Italy on a cohort of 545 patients taking ART and either atorvastatin or rosuvastatin. The primary study goal was to evaluate the association between vitamin D level and muscle toxicity using the following markers: myalgia, elevated creatinine kinase level in the absence of myalgia, or myalgia and elevated creatinine kinase level.

The majority of patients were male (80%) and white (91%); 95% had an undetectable viral load. Muscle toxicity was identified among 100 patients (18%), evidenced by myalgia in 42, elevated creatinine kinase without myalgia in 33, and elevated creatinine kinase with myalgia in 25. There was no statistically significant difference in muscle toxicity between patients taking atorvastatin or rosuvastatin. The median time to muscle toxicity was 412 days, with 10% of patients having toxicity within 34 days of starting a statin. Vitamin D deficiency was associated with muscle toxicity. Among patients with muscle toxicity, the vitamin D level was 19 to 22 ng/mL (depending on presence of myalgia or elevated creatinine kinase level), compared with a level of 32 ng/mL among patients without muscle toxicity. Among the 40 patients with a vitamin D level available at the time of myalgia or elevated creatinine kinase diagnosis, the level was similar to that at baseline. In an adjusted analysis, factors associated with muscle toxicity were age older than 60 years, history of myalgia, vitamin D levels lower than 30 ng/mL (odds ratio, 2.3), and longer duration on statin therapy. Notably, therapy with a boosted-protease inhibitor was not associated with an increased myalgia risk.

Two observational studies in the general population suggest that supplementing vitamin D when the level is low may reduce the occurrence of statin-related myalgia [Glueck CJ, et al. Curr Med Res Opin. 2011 Sep;27(9); Khayznikov M, et al. N Am J Med Sci. 2015 Mar;7(3)]. Randomized trials of vitamin D supplementation to reduce statin myalgia have not been completed in the general population or among people living with HIV. However, given the frequency of vitamin D deficiency in patients living with HIV and the potential benefits of a normal vitamin D level on bone health and immune activation [Overton ET, et al. Ann Intern Med. 2015 Jun16;162(12); Fabre-Mersseman V, et al. AIDS. 2014 Nov 28;28(18)], treating vitamin D deficiency with oral vitamin D3 supplementation is reasonable. Achieving a normal vitamin D level may also reduce statin-induced myalgia, increasing the chance of success with statin therapy and ultimately reducing cardiovascular disease.  

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Quality of Life Improvement with Early ART Initiation (2/17)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University School of Medicine 

Results of a just-published study suggest that, in addition to reducing all-cause mortality and improving health overall for patients with HIV infection, early initiation of ART also improves quality of life (QOL). Using data collected at baseline and during follow-up visits for the START trial, Lifson and colleagues assessed whether timing of ART initiation affected patients’ self-assessed QOL (Lifson, AR et al. AIDS. 2017 Apr 24;31(7)).

The START trial, which was conducted in 35 countries, randomized 4,685 participants with CD4 counts >500 cells/mm3 to one of 2 arms: immediate ART initiation or ART initiation at CD4 count <350 cells/mm3. Roughly 50% of participants lived in high-income countries and 50% in low- and middle-income countries. Approximately 75% received an initial ART regimen containing efavirenz, an agent well known to cause CNS and mood side effects.

At each study visit, patients were asked to assess their QOL using 2 methods–a visual analog scale to record their perceived current state of health (scored 0-100) and the SF-12, a widely used survey that includes physical and mental health components. 

QOL data were collected for 4,561 START trial participants, distributed evenly between the immediate and deferred ART study arms. At baseline, physical and mental health scores were similar between the two arms. By 4 months they diverged, with scores improving in the immediate ART arm and remaining relatively unchanged in the delayed ART arm. Scores of deferred ART patients were censored from analysis upon ART initiation.

The difference in QOL scores persisted: throughout 5 years of follow-up; when individuals with severe events were excluded; and through multiple subgroup analyses, including age, gender, race, geographic region, baseline CD4 count, efavirenz ART, and baseline visual analog scale.

This analysis provides further support for universal access to ART upon diagnosis of HIV infection: ART reduces severe health events, reduces HIV transmission, and improves quality of life for otherwise healthy people living with HIV.  

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A High Rate of Dolutegravir Side Effects in "Real-World" Settings (1/17)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University School of Medicine 

In my practice, 5% to 15% of the patients I start on dolutegravir (DTG) experience intolerable headaches or insomnia that necessitate a switch to another agent. This level of intolerance is higher than reported from clinical trials. I always wonder whether the patients of other clinicians have had the same “real-world” experience with DTG side effects and now several recent studies shed light on this issue. 

In one study, researchers from the Netherlands [de Boer MG, et al. AIDS. 2016 Nov 28;30(18)] reported on the tolerability of DTG among 556 patients initiated on DTG between August 2014 and March 2016. DTG was stopped in 76 patients (13.7%) due to adverse drug reactions after a median of 73 days (range 5-327). The combination of DTG with abacavir (ABC) led to a higher overall discontinuation rate (16.3%). The majority of side effects were neuropsychological or psychiatric (insomnia, headaches, mood alterations, and malaise) and gastrointestinal. Discontinuation for neuropsychiatric side effects was 2.3 times more likely among patients taking DTG plus ABC.

Other researchers have also reported neuropsychiatric side effects with DTG. Researchers in Germany [Hoffmann, C et al. HIV Med. 2017 Jan;18(1)] evaluated a cohort of 1,704 patients who initiated an ART regimen containing an integrase strand transfer inhibitor (ISTI) between January 2007 and April 2016. The rates of adverse events leading to discontinuation within 12 months were 7.6% for elvitegravir (EVG), 7.6% for DTG, and 3.3% for raltegravir (RAL). Renal side effects were the leading cause of EVG discontinuation (3.5%); neuropsychiatric side effects were most commonly reported with DTG (5.0%). The most common neuropsychiatric symptoms among the 49 patients who discontinued DTG were insomnia and other sleep disturbances, dizziness, headache, poor concentration or slowed thinking, depression, and painful paresthesia.

An older (2015) case series from France that includes four patients [Kheloufi, F et al. AIDS. 2015 Aug 24;29(13)] described the following symptoms post-DTG-initiation: fatigue and “drunk feeling” in patient 1, headaches and depression in patient 2, worsening psychiatric symptoms in patient 3, and intense headaches (which spontaneously resolved) followed by suicidal ideation in patient 4. 

DTG is a highly potent agent with a high barrier to resistance and unparalleled outcomes in randomized trials [Cahn, P et al. Lancet. 2013 Aug 24;382(9893); Clotet, B et al. Lancet. 2014 June 28;383(9936); Walmsley, SL et al. N Engl J Med. 2013 Nov 7;369(19)], and it appears to be very well tolerated in most patients who do not experience side effects. For these reasons, it has an important role in current antiretroviral therapy (ART). However, assessing for side effects and correctly identifying DTG as a potential cause of new and unexpected symptoms in the days to weeks after initiating this drug is essential to optimal care. My experience with the side effects with DTG has taken a little of the shine off this potent agent and has led me to consider the potential for DTG-associated side effects when selecting a regimen for an ART-naïve patient or planning a switch for failure or convenience.    

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Is Memory Really the Problem in ART Adherence? (10/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University

An undetectable HIV viral load is the sine qua non of effective antiretroviral therapy (ART). Once the correct ART regimen is prescribed, achievement of an undetectable viral load then depends on sustained adherence. The authors of a recent study in AIDS Care (Kalichman SC, et al. AIDS Care. 2017 Apr;29(4).) sought to better understand and differentiate between factors associated with moderate and severe non-adherence. Moderate non-adherence was defined as 75% to 95% of medication doses taken as prescribed; severe non-adherence was defined as <75% of doses taken as prescribed.

The authors used computerized interviews to collect patient self-reported data on symptoms, side effects, use of common reminder strategies, depression, life stress, and alcohol consumption. The authors also used urine testing to assess for recent illicit drug use. Over a 1-month period, participants were contacted three times for telephone-based pill counts. Participants who had missed doses were then asked about cognitive, organizational, mental health, substance use, and structural barriers to adherence. 

The team followed 214 severely non-adherent and 342 moderately non-adherent participants for 1 month. A large and equal proportion of patients in each group used memory aids to support adherence, including pill boxes, alarms, routine timing of pills, journals, reminders from family members, or posted reminder signs. Although a larger proportion of the severely non-adherent participants reported having forgotten or having been too busy to take medications, the number was not statistically significant. Of the severely non-adherent, 54% reported forgetting compared with 41% of the moderately non-adherent. A larger and statistically significant difference in adherence was related to side effects, running out of pills, and consumption of alcohol (see table below). Depression and stress were also higher among severely non-adherent participants.

Factors Affecting ART Adherence Participants Reporting this Effect,          by Level of Non-Adherence
Severe Moderate
Medication side-effects 12% 4%
Running out of pills 21% 9%
Consumption of alcohol 21% 13%

The results of this study suggest that even when adherence reminder strategies are used, they are not effective in helping patients overcome factors related to both severe and moderate non-adherence, including, in this group, alcohol use, access to medications, and mental health challenges. 

This study did have some limitations. The researchers followed participants for just 1 month, and the results were not strong: 68% of the severely non-adherent had undetectable viral loads, and less than 50% of non-adherence among participants was associated with the factors named above.

Nonetheless, the results highlight the roles that mental health, substance use, and structural barriers may play in reducing adherence to ART. The findings also suggest that other, yet-to-be identified factors are at play as well. Perhaps most importantly, the standard focus on memory, reminders, and memory aids may not be helpful in significantly improving adherence among those with demonstrated non-adherence, and we need to dig deeper to help our patients take the medications that will suppress their viral loads.

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Successful Same-Day ART Initiation with a Complex Patient Population (8/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University

A move to test and initiate treatment on the same day will require changes in traditional approaches to HIV management. Those changes may include restructuring clinic services and identifying individuals who are the best candidates for immediate antiretroviral therapy (ART) initiation. A recent article (Pilcher et al. J Acquir Immune Defic Syndr. 2017 Jan 1;74(1)) describing immediate ART initiation by the San Francisco General Hospital outpatient HIV clinic provides insight into both issues.

Beginning in July 2013, the clinic began to offer same-day ART initiation with a protocol called RAPID. During the entire reported period (6/2013 to 12/2014), only patients lacking private insurance were eligible. In the first 6 months, eligibility for RAPID care was also limited to patients with acute or recent HIV infection, but criteria were liberalized after January 2014. Patients were referred from outpatient clinics and HIV testing centers in San Francisco, and taxi vouchers were available for patients to be transported from across the city. 

The RAPID protocol provided same day HIV education, blood draws for laboratory testing, accelerated insurance approval efforts, and a directly observed first ART dose. Patients for whom insurance approval was not obtained were given a 5-day starter-pack. This process took 3 to 4 hours. Within the 7 days after the initial visit, a nurse followed up by phone.

During the 18 month study period, 39 patients who would be considered “complicated” in most treatment settings were initiated on the RAPID protocol (2 patients per month). Patients’ CD4 counts ranged from 3 to 1391 cells/mm3, 27% were considered homeless, 42% had a “major” mental health disorder, and 42% reported use of any illicit substance. Despite these challenges, 37 patients (95%) initiated ART within 24 hours of their clinic visit. Approximately 90% had a viral load <200 copies/mL within 6 months after clinic referral. Only 4 (10%) were lost from care (no visit in a 6 month period); 8 (20%) transferred care to another clinic.

Although limited by its very small sample size and low volume of patients during the observation period (2 patients per month), this report is valuable for its description of a same-day ART initiation program that succeeded with complex patients. With the right clinical resources, these results suggest that most people living with HIV can initiate ART rapidly with success. This report also underscores that ART should not be delayed automatically because of mental illness, substance abuse, and/or unstable housing. 

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Blood Pressure Control and Medication Adherence among People Living with HIV (7/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University

Hypertension is a common comorbidity among people living with HIV (PLH), affecting 20% to 43%. This proportion is likely to grow with the aging of the PLH population (see Okeke NL, et al. Clin Infect Dis 2016 Jul 15;63(2), for time trends in HTN diagnosis among PLH). Recent studies suggest the need to educate patients about the risks of uncontrolled hypertension (HTN).

The pivotal 2015 SPRINT study [SPRINT Research Group, et al. NEJM 2015 Nov 26;373(22)] quantified a reduction in mortality and cardiovascular outcomes with tight versus routine HTN control among individuals who were not HIV-infected. This large, randomized, controlled trial involved 9,361 individuals 50 years of age and older with a systolic blood pressure (SBP) between 130 and 180 mmHg (median 140 mmHg) and cardiovascular risk factors other than diabetes. Participants were randomized to one of two arms, with results reported after a median 3.3 years of follow-up. Results are summarized in the table below.

  Treatment Arm
Participants Standard Intensive
Number 4,683 4,678
Target SBP mmHg <140 <120
Median no. HTN meds 1.8 2.8
Serious adverse events 2.5% 4.7%
No. reaching primary clinical outcome
(hazard ratio = 0.75, p < 0.001)
319 243

The primary clinical outcome was defined as one of the following: myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. All-cause mortality was also substantially lower (hazard ratio = 0.73, p = 0.003) in the intensive treatment arm. Approximately 38% of participants in each arm experienced side effects, although serious adverse events, such as hypotension, syncope, electrolyte abnormalities, and acute kidney injury, were higher in the intensive treatment arm. In all, the SPRINT study demonstrated that a goal of SBP<120 mmHg reduced mortality and cardiovascular outcomes among individuals over the age of 50.

The PLH population already on antiretroviral therapy (ART) has experience with multiple medications and with regimens that require adherence as strict as those for HTN. 

Weiss and colleagues [J Acquir Immune Defic Syndr. 2016 Dec 1;73(4)] recently studied the effects of adding both medications and exhortations for strict adherence to the treatment regimens of HIV-infected participants. The researchers recruited 117 participants with HIV and HTN and 37 participants with HIV and chronic kidney disease (CKD) and followed them with health belief surveys and electronic monitoring of adherence to HIV, HTN, and CKD medications. At the 10 week follow-up, 88% of participants had virologic control and 60% had HTN control (SBP<140 mmHg). However, there was no difference in adherence to ART and HTN medications.

ART adherence was associated with participants’ reports of greater understanding of HIV, the perception of greater severity of HIV, and the view that ART medications are more necessary than medications for other conditions. This study suggests that HTN control is worse than virologic control among PLH, even though adherence to the two types of medication may be similar.

Taken together, the results of these two studies suggest that clinicians caring for PLH may need to intensify efforts to educate patients about HTN and its consequences and the potential benefit of a blood pressure even lower than the standard <140 mmHg. 

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Cardiovascular Risk Scores and CVD Risk Reduction among People Living with HIV (6/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University

Primary methods of preventing cardiovascular disease (CVD) with smoking cessation, control of hypertension, and use of aspirin and HMG-CoA reductase inhibitors can substantially reduce the risk of myocardial infarction. Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend risk-based prescription of HMG-CoA reductase inhibitors. The ACC/AHA guidelines use a specific population-based risk calculator; however, other scores are also available, including the Framingham Risk Score and the D:A:D cardiac risk score for people living with HIV (PLH). Among PLH, it remains unclear how well these scores predict risk of myocardial infarction caused by plaque rupture.

Monroe and colleagues [Monroe AK, et al. AIDS. 2016 Aug 24;30(13)] used data from the Multicenter AIDS Cohort Study (MACS), a multisite longitudinal cohort of HIV-infected and -uninfected men who have sex with men, to assess the performance of risk calculators for predicting coronary atherosclerosis, coronary calcium, or coronary stenosis of greater than 50%, as measured using cardiac computed tomography (CT). The authors reported a poor association between cardiac risk score and the presence of any plaque (area under the curve is 0.65 for PLH; an area under the curve of 0.5 indicates no correlation). Among PLH who were at low risk according to the ACC/AHA formula, 36% had a coronary artery calcium score greater than 0, 63% had any plaque (calcified and non-calcified), and 11% had greater than 50% stenosis. Performance was marginally better for those without HIV infection; however, 53% with any plaque and 5.4% with greater than 50% stenosis were in the low-risk category.

There are several potential interpretations of these findings:

  • The MACS population is different from everyone else, and risk calculators do not apply.
  • Compared with the general population, PLH have different needs and risk profiles for some aspects of primary care, such as CVD risk management, and calculators may not be the best approach to CVD risk management in PLH.

Limitations of this study include its use of a cohort that is not representative of the general PLH population and its use of coronary calcium score and atherosclerosis on CT as opposed to hard endpoints, such as CVD events.

Studies such as this raise questions regarding use of HMG-CoA reductase inhibitors among PLH. In other words, are we treating the right people? The ongoing REPRIEVE clinical trial is aimed at helping to answer this question.

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Predicting Kidney Disease Risk to Guide ART Selection (4/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University

Kidney disease is common among people living with HIV. Multiple factors, including HIV-associated nephropathy, antiretroviral therapy (ART), hepatitis B (HBV) or C (HCV) virus coinfection, diabetes, hypertension, and primary kidney disease can cause or contribute to kidney dysfunction. More common factors, though, are transient fluctuations in serum creatinine and estimated glomerular filtration rate (eGFR). Reducing the occurrence of comorbidities associated with kidney disease and limiting the diagnostic uncertainty of eGFR fluctuations may influence ART-prescribing decisions.

In a recently published article [AIDS 2016 Jun 1;30(9)], Flandre and colleagues report on the relationship between various initial ART regimens and the risk of chronic kidney disease (CKD). The researchers used a predictive score, developed and validated through the D:A:D cohort, that defined CKD as a persistent eGFR <60 mL per min per 1.73 m2.

The study cohort included 6,301 patients receiving care at 12 reference centers in France, all of whom initiated ART after January 1, 2004. All patients had at least one pre-ART and two on-ART creatinine measures, and eGFR was determined with the MDRD equation. Patients were stratified into low, medium, and high risk for CKD using the D:A:D score for CKD. This score accounts for a wide variety of factors, including type of HIV exposure (injection drug use [IDU] vs non-IDU), HCV coinfection, age, pre-ART eGFR, sex, nadir CD4 count, hypertension, cardiovascular disease, and diabetes. Incident CKD occurred in 211 (3.4%) of participants and was associated with older age, lower pre-ART eGFR, and lower nadir CD4 count. The probability of CKD by risk score was as follows: low risk, 0.65%; medium risk, 4.6%; and high risk, 15.9%.

CKD risk was highest for patients receiving a boosted protease inhibitor (PI) with tenofovir disoproxil fumarate (TDF). Risk was lower for patients receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI) with or without TDF. Notably, among low-risk patients, the choice of an NNRTI vs a PI or TDF vs no TDF made no apparent difference in CKD risk.

This study is helpful in assessing the appropriateness of TDF or boosted-PI regimens for specific patients. For instance, avoidance of an initial ART regimen that includes TDF or a boosted-PI may be best for patients with a high D:A:D score for CKD. Patients with a low CKD risk score do not appear at increased risk for CKD from TDF or boosted PIs. These types of data may also be useful in securing insurer authorization to prescribe specific medications, such as tenofovir alafenamide (TAF)-containing combination tablets, and in discussing ART regimen side-effect profiles with patients.

Taking a risk-based approach when choosing an ART regimen does not require actual calculation, but taking into account a patient’s D:A:D score and risk factors for CKD is encouraged. Such an approach may reduce the number of patients requiring switches to less nephrotoxic regimens due to elevated eGFRs and may reduce the incidence of CKD among people living with HIV.

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Life Expectancy after an HIV Diagnosis (3/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University

One of the first questions a patient newly diagnosed with HIV may ask is, “How long will I live?” A new study from CDC researchers, which reports data on life expectancy from the time of diagnosis and average years of life lost (AYLL)*, may help in answering that question [Siddiqi, et al. J Acquir Immune Defic Syndr 2016 Jun 1;72(2)].

Using CDC HIV Surveillance Report data from all 50 US states and the District of Columbia, the researchers estimated life expectancy by year of HIV diagnosis for individuals reported to have been diagnosed during the four years from 2008 to 2011.  Life expectancy was further stratified by HIV exposure category, sex, and race/ethnicity.  The authors did not consider post-diagnosis factors such as engagement in care or virologic suppression.

Overall, between 2008 and 2011, the average life expectancy at the time of HIV diagnosis increased by 3.5 years, from 25.4 to 28.9 years. By transmission category, life expectancy at the time of diagnosis in 2011 was highest (32.3 years) among men having sex with men (MSM); it was lowest (20.2 years) among men injecting drugs. Analysis by race indicated that life expectancy was highest among Hispanic/Latinos, followed by blacks, whites, and other races (range: 26.1 to 30.8 years). Average years of life lost were not similarly stratified. With regard to sex, for all men diagnosed at age 25, the AYLL was 16.8 years; for women diagnosed at age 25, AYLL was 23.2 years.

This analysis demonstrates continued overall improvement in HIV survival, which may reflect increasing efforts to engage people living with HIV in care and to initiate antiretroviral therapy (ART). However, the analysis also highlights discrepancies in survival by population group, which most likely reflects better engagement in care among MSM than among injection drug users. And while the study reinforces the value of ART for achieving longevity, its findings suggest that nearly normal life expectancy with HIV infection depends not only on access to ART for all patients but also on support to overcome systemic social, economic, and substance use challenges and maintain engagement in care and adherence to ART.

*AYLL is calculated by subtracting life expectancy with HIV from life expectancy for the general population. 

Detection of Invasive Anal Cancer in HIV-Infected Patients (1/16)

By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University School of Medicine

Although invasive anal cancer is relatively rare, the disease can be devastating. The incidence of this cancer is increased among people living with HIV, especially among those who engage in receptive anal sex. For someone living with HIV in the United States or Canada, the cumulative incidence for anal cancer by the age of 65 has been estimated to be 1.3% compared with 0.03% for someone without HIV [Silverberg et al., Ann Int Med 2015 Oct 6;163(7)]. This cumulative incidence exceeds those for colorectal, liver, and pharyngeal cancer.

Clinical guidelines for prevention of anal cancer borrow heavily from the cervical cancer literature, with limited data to support specific screening and management practices. Routine screening generally includes anal cytology without HPV typing. A recent article by D’Souza and colleagues adds to the knowledge base of anal cancer. They studied the incidence and clearance of squamous intraepithelial lesions, as well as high-risk HPV infection, among HIV-infected and uninfected men who have sex with men (MSM) in the United States [J Acquir Immune Defic Syndr. 2016 Apr 15;71(5)]. The authors describe longitudinal follow-up for 1511 men with repeat anal cytology separated by 2 years; 723 were living with HIV; 788 did not have HIV. Most of those with HIV had undetectable viral loads (78%), and the median CD4 cell count was 583 cells/mm3. Abnormal cytology (of any kind) was identified among 40% of the men living with HIV and in 25% of those without HIV. Only 1.5% of men had high-grade squamous intraepithelial lesions. However, 2.4% had atypical squamous cells for which high-grade lesions could not be excluded. Among HIV-infected men who received repeat cytologic testing after initial ASCUS (atypical cells of undetermined significance) or low-grade squamous intraepithelial lesions, 56% regressed to normal cytology; 81% of those with high-grade cytologic findings regressed to a lower grade. High-risk HPV 16 was identified among 25% of men living with HIV and 16% of those without HIV. Among 220 men who received follow-up high-resolution anoscopy with biopsy after cytologic findings of high-grade lesions, 17% had histologically confirmed disease.

This study adds to the data on the high prevalence of anal HPV infection and cellular changes among MSM with HIV. It also highlights the limitation of cytology to identify individuals who should receive high-resolution anoscopy and biopsy, given the frequency of regression of lower-grade lesions to normal. Additional studies are underway that could shed more light on prevention of anal cancer and management of high- and low-grade lesions. Until results are available from those studies, the common practice of routine cytologic testing and referral for high-grade lesions, as well as for atypical squamous cells for which high-grade lesions cannot be excluded, remains a reasonable approach.

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