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Insulin Resistance, Low risk of Efavirenz Rash after NVP Rash, Preventing Newfill/Sculptra Papules
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Written for NATAP: A report from the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy
Mark Mascolini
- Predictors of insulin resistance in first year of therapy
- Low rash risk with efavirenz after nevirapine rash
- Three measures confirm 144-week renal record of tenofovir
- Massage prevents papules with Sculptra/NewFill
Predictors of insulin resistance in first year of therapy
Studying 120 people during their first 48 weeks of antiretroviral therapy, clinicians from Malaga and Seville turned up two baseline predictors of insulin resistance—HCV infection and treatment with indinavir—and two associated factors that evolved during antiretroviral therapy—higher weight and a diagnosis of lipodystrophy [1].
These clinicians tracked 120 people at two HIV clinics who started their first antiretrovirals from June 2002 through June 2003 and stayed with the same regimen for 48 weeks. Everyone had 95% or better antiretroviral adherence, no one had diabetes, and no one took other drugs that could tip a person’s glucose-insulin balance.
Ninety-one cohort members (76%) were men, 69 (66%) smoked, 43 (36%) had HCV infection, and 16 (21%) had a family history of diabetes. Before these people started antiretrovirals their CD4 count averaged 222 cells/mm3 (interquartile range 64 to 313 cells/mm3) and their viral load averaged 5.39 log (about 245,500) copies/mL.
After 48 weeks of therapy, 81% had an undetectable viral load, while the average CD4 count climbed 182 cells/mm3. Most metabolic variables measured strayed significantly in the wrong direction in these 48 weeks. Average total cholesterol climbed from 154 to 191 mg/dL, and menacing low-density lipoprotein cholesterol from 93 to 114 mg/dL (P = 0.0001 for both changes).
The group’s average glucose rose from 90 to 95 mg/dL (P = 0.0001) and insulin from 7.24 to 10.15 microUI/mL (P = 0.002). Average body mass index edged up from 23.1 to a still-normal 24.5 kg/m2. After 48 weeks of antiretroviral therapy, 15 people (13%) had insulin resistance, defined as a HOMA score above 3.8.
Multivariate analysis settled on four factors that independently raised the risk of insulin resistance (Table). These researchers did not explain how they defined lipodystrophy, one of the two 48-week variables linked to insulin resistance.
Predictors of insulin resistance in 120 people starting antiretrovirals
Higher triglycerides correlated with insulin resistance in the univariate analysis, but smoking, family history of diabetes, and baseline glucose did not. People who ended up with insulin resistance had a higher pretreatment insulin reading in the univariate analysis (9.2 versus 6.8 microUI/mL in people who stayed free of insulin resistance, P = 0.01). Insulin resistance developed in none of 19 people who took a nevirapine-based regimen.
Low rash risk with efavirenz after nevirapine rash
Only 10 of 122 adults (8%) who replaced nevirapine with efavirenz because of rash had the same problem with the second nonnucleoside, Thai clinicians reported [2]. They could tease out no predictors of efavirenz-induced rash after a nevirapine rash.
Weerawat Manosuthi from the Ministry of Public Health in Nonthaburi and coworkers checked records of 122 people, 64 of them (52.5%) men, who had to stop nevirapine because of rash. These people started their nevirapine regimens with a low median CD4 count of 54 cells/mm3 (interquartile range 20 to 167 cells/mm3). Seventy-six people (62%) dropped nevirapine because of diffuse maculopapular rash or urticaria, and 46 (38%) did so because of rash with constitutional symptoms, angioedema, serum sickness-like reactions, or Stevens Johnson syndrome.
Another rash flared up in 10 people a median of 8 days (interquartile range 2.0 to 12.3 days) after the switch to efavirenz. Stevens Johnson syndrome arose in 1 person with a history of multiple drug allergies, while the other 9 had diffuse maculopapular rash of the trunk and limbs. All rashes cleared after indinavir/ritonavir replaced efavirenz.
Checking a laundry list of variables that may favor a second rash, the Thai team found none. Nonpredictive factors included age, gender, baseline CD4 count, baseline viral load, previous opportunistic infections, severity of nevirapine-induced rash, time between stopping nevirapine and starting efavirenz, and concurrent medications. The 10 people who got a second rash were slightly but not significantly older than those who did not (40.5 versus 36.5 years, P = 0.167).
Three measures confirm 144-week renal record of tenofovir
Two formulas to calculate glomerular filtration rate—a signal of kidney trouble—figured no significant change during 144 weeks of tenofovir therapy in the randomized trial comparing tenofovir with d4T [3]. Development of chronic kidney disease, as defined by the National Kidney Foundation, did not differ between the tenofovir and d4T groups.
With coworkers in Germany and Britain, Joel Gallant from Johns Hopkins University in Baltimore ran this 144-week, double-blind, placebo-controlled trial of tenofovir or d4T plus 3TC and efavirenz in 600 previously untreated people. The trial excluded people with pretreatment portents of kidney problems.
Gallant used the Cockcroft-Gault equation and the Modification of Diet and Renal Disease (MDRD) formula to figure glomerular filtration rates in the two study arms at study week 144. A lower Cockcroft-Gault or MDRD score indicates worse creatinine clearance. Gallant noted that either equation gauges kidney function better than simply measuring serum creatinine, though the MDRD seems more accurate in people without HIV who have chronic kidney disease. But the MDRD formula has not been validated in people with normal kidney function or in people with HIV. (See note 4 for the equations. Online Cockcroft-Gault and MDRD calculators can be found at http://nephron.com/mdrd/default.html.)
Baseline glomerular filtration rates by either equation and National Kidney Foundation kidney disease stage proved similar in the two treatment arms. After 144 weeks of tenofovir or d4T, glomerular filtration rates did not change significantly in the tenofovir group, though they did rise significantly among people taking d4T (Table).
Glomerular filtration rates at 144 weeks in the tenofovir-vs-d4T trial
Glomerular filtration rate reckoned by the Cockcroft-Gault equation did not change significantly in either treatment arm among people taking antihypertensives or antidiabetes drugs during the study.
No one in the trial stopped tenofovir because of kidney problems, and study clinicians never diagnosed proximal renal tubular dysfunction or Fanconi syndrome through 144 weeks.
In a separate retrospective look at clinical trial data, Glaxo researchers unearthed no evidence of significant changes in glomerular filtration rate after previously untreated people took efavirenz plus Trizivir (AZT/3TC/abacavir), Combivir (AZT/3TC), or 3TC/abacavir for 48 weeks [5].
Massage prevents papules with Sculptra/NewFill
Massage immediately after injection of polylactic acid (Sculptra or NewFill) for facial lipoatrophy—then daily massage for 1 month—dramatically lowered the number of subcutaneous papules resulting from this procedure [6].
Patrick Unemori from the University of California, San Francisco and colleagues treated 24 men with polylactic acid for moderate to severe facial atrophy, giving monthly injections until both the men and the physician were satisfied with results. The men received a median of 8 treatments (interquartile range 5.25 to 10.75) with a median total of 66.5 cm3 of PLA (interquartile range 45.88 to 91.25 cm3).
During the course of these procedures, Unemori and colleagues began a massage protocol, which involved 5 minutes of firm massage, sometimes with a vibrator, to spread polylactic acid from each injection site. The men were told to massage the injection areas 10 minutes twice a day, or 5 minutes five times a day, for 1 month. (See note 7 for the complete procedure.)
Median papule formation before the massage protocol began measured 0.14 per cm3 of polylactic acid (interquartile range 0 to 0.25 per cm3 of polylactic acid). After the massage protocol began, median papule formation measured 0.0 per cm3 of polylactic acid (interquartile range 0.0 to 0.0357 per cm3 of polylactic acid), a highly significant difference (P < 0.001). The 5 men enrolled in the study after massage became routine had a total of 6 papules (0.028 papules per cm3 of polylactic acid).
Mark Mascolini writes about HIV infection
References and Notes
1. Palacios R, Merchante N, Macias J, et al. Prospective study of glucose metabolism in antiretroviral naive HIV-infected patients: incidence of insulin resistance at 48 weeks of HAART. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-344.
2. Manosuthi W, Thongyen S, Chumpathat N, et al. Prevalence and risk factors of rash from efavirenz in HIV-infected patients with preceding nevirapine-associated rash.
45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-343.
3. Gallant J, Staszewski S, Pozniak A, et al. Similar renal safety profile between tenofovir DF and stavudine (d4T) using modification of diet in renal disease and Cockcroft-Gault estimation of glomerular filtration rate in antiretroviral-naive patients through 144 weeks. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-350.
4. Cockcroft-Gault equation: glomerular filtration rate (mL/min) = (140 - age in years) x weight in kg divided by (72 x serum creatinine in mg/dL) x (0.85 if female).
Modification of Diet in Renal Disease equation: glomerular filtration rate (mL/min/1.73 m2)= 186 x serum creatinine in mg/dL(-1.154) x age in years(-0.203) x 0.742 if female x 1.212 if black.
5. Sutherland-Phillips D, Hill-Zabala C, Brothers Q, et al. Regimens containing abacavir, lamivudine, zidovudine, and efavirenz do not affect glomerular filtration rate during long-term treatment of HIV-naive subjects. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-349.
6. Unemori P, Eden C, Conant M. Treatment of HIV-related facial lipoatrophy: incidence of subcutaneous papules resulting from polylactic acid treatment decreases with facial massage. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-341.
7. The complete polylactic acid massage procedure described by Unemori and colleagues (reference 6) follows: (1) Dilute Sculptra [polylactic acid] with 5 cm3 bacteriostatic water and 1 cm3 2% xylocaine. (2) Prepare 12 to 24 hours before injection and refrigerate. (3) Administer with 3- cm3 syringe and 25-gauge needle. (4) If needle is obstructed, change needle to avoid bolus. (5) Inject 1.5 cm3 in temples (if needed) below muscle. (6) Inject 5 cm3 in chin (if needed) at dermal-fat junction. (7) Inject 3 cm3 to 5 cm3 in cheeks. (8) Injections must be small drops (0.05 cm3) at multiple sites. One cm3 = 20 drops. It is not a filler. It is a matrix for collagen formation. (9) Massage very firmly to spread out Sculptra [polylactic acid] after injections for 5 minutes at each site. Vibrator helps. (10) Have patient massage for 10 minutes twice a day for 1 month of 5 minutes five times a day for 1 month.
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