Amy E. Colson

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).

HIV-1 genotypic zidovudine drug resistance and the risk of maternal-infant transmission in the women and infants transmission study.

ObjectivesAlthough the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. MethodsThe reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. ResultsTwenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P  = 0.0001) and higher plasma HIV-1 RNA (P  = 0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P  = 0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P  = 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P  = 0.009] were independently associated with transmission in multivariate analysis. ConclusionMaternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients.

Background: Agents for the treatment of HIV-1-infected patients with resistance to current antiretroviral (ART) drugs are needed. Methods: TMC114-C202 was a randomized, partially blinded, dose-finding study in treatment-experienced HIV-1-infected patients with one or more primary protease inhibitor (PI) mutations and HIV-1 RNA > 1000 copies/ml. Patients were randomized to receive one of four TMC114 doses given with ritonavir (TMC114/r) or investigator-selected control PI drug(s) (CPI); all received an optimized background regimen. The primary intent-to-treat analysis compared the proportion of patients achieving a ≥ 1 log10 copies/ml HIV-1 RNA reduction at week 24 between the treatment arms using the time-to-loss of virological response algorithm. Results: For 278 patients at baseline, mean HIV-1 RNA was 4.7 log10 copies/ml, median CD4 cell count was 106 cells/μl; HIV-1 isolates had a median of three primary PI mutations and a median fold change in lopinavir susceptibility of 80. Discontinuation rates were 23% for TMC114/r versus 64% for CPI. More patients in each TMC114/r dose group achieved ≥ 1.0 log10 copies/ml reduction in HIV-1 RNA than in the CPI group (45–62% versus 14%; P ≤ 0.003): patients taking TMC114/r twice daily had the greatest responses. HIV-1 RNA was < 50 copies/ml in 18–39% of TMC114/r patients versus 7% CPI (P < 0.001 for highest dose). Mean CD4 cell count increased by 59–75 versus 12 cells/μl (TMC114/r versus CPI: P ≤ 0.005). Overall adverse event rates were similar in both arms, without significant differences among TMC114/r groups. Conclusions: TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks.

Male sexual dysfunction associated with antiretroviral therapy.

To determine whether treatment with protease inhibitors (PIs) is associated with male sexual dysfunction, we conducted a retrospective, cohort study of 254 adult male PI recipients who received care from the staff-model division of a large managed care organization in New England between 1993 and 1998. After a median of 5.0 years of observation, 80 incident cases of sexual dysfunction were observed. Relative to unexposed individuals, the rate of sexual dysfunction adjusted for confounding was most elevated with use of ritonavir (hazard ratio [HR], 2.83; 95% confidence interval [CI], 1.34-5.97; p =.006) followed by indinavir (HR, 1.69; 95% CI, 0.84-3.37; p =.14), nelfinavir (HR, 1.53; 95% CI, 0.66-3.54; p =.32) and saquinavir (HR, 1.25; 95% CI, 0.53-2.96; p =.60). We conclude that PIs, especially ritonavir, appear to increase the risk of sexual dysfunction.

Pilot Study of a Novel Short-Cycle Antiretroviral Treatment Interruption Strategy: 48-Week Results of the Five-Days-On, Two-Days-Off (FOTO) Study

Abstract Purpose: The challenges associated with daily lifelong antiretroviral therapy (ART) have stimulated interest in alternative treatment schedules, including planned, cyclical interruptions of therapy in patients with virologic suppression and sufficient CD4+ T-cell counts. Method: We conducted a 48-week, open-label, single-arm, prospective pilot study of a novel short-cycle treatment interruption strategy. Upon enrollment, 30 HIV+ individuals with a history of durable viral suppression on daily ART changed their weekly treatment schedule to 5 consecutive days on treatment (typically Monday through Friday) followed by 2 days off treatment (five-on, two-off, or FOTO treatment schedule). Results: At 24 and 48 weeks, as-treated analysis revealed that virologic suppression was maintained in 26/29 subjects (89.6%), including 100% of subjects taking efavirenz-based regimens. Participants adhered well to the FOTO treatment schedule and expressed a strong preference for the FOTO treatment schedule compared to daily ART. Conclusion: If validated, the FOTO treatment strategy with efavirenz-based regimens could avoid the viremia witnessed in longer cycle structured treatment interruptions yet still ameliorate a number of problems associated with the current paradigm of daily ART for HIV infection, including the high cost of therapy and the pill fatigue that, in many patients, leads to erratic adherence and ultimately treatment failure

Paronychia in association with indinavir treatment.

To assess a possible association between antiretroviral treatment and paronychia, we conducted a retrospective cohort study of 288 human immunodeficiency virus-positive protease inhibitor recipients. Indinavir treatment-adjusted for age, sex, CD4 count, diabetes status and other antiretroviral drug exposures-was significantly associated with paronychia of the great toe (hazard ratio 4.7; 95% confidence interval 1.6-13.9).

Sexual dysfunction and HIV infection.

Although complaints about sexual dysfunction are common in persons with HIV infection, the epidemiology and mechanisms of sexual dysfunction in this

Similar efficacy of raltegravir when used with or without a protease inhibitor in treatment-experienced patients.

Abstract Background: Patients with multiclass-resistant HIV-1 have limited treatment options. Raltegravir, an inhibitor of integrase, has shown excellent efficacy when used with protease inhibitors (Pis) in patients with drug-resistant HIV-1. Limited data are available however about the outcomes when using raltegravir without Pis in this population. Methods: Medical records of subjects who received raltegravir as part of the Merck EAP study 0518 were reviewed and abstracted at participating sites. Eligibility criteria included HIV positivity, age ≥16 years, limited or no treatment options due to resistance or intolerance to multiple antiretroviral regimens, detectable viremia on current treatment regimen, and documented resistance to at least one drug in each antiretroviral class (PI, NNRTI, and nucleoside analogue). Demographic, clinical, and laboratory data were collected locally using a standardized collection form. Genotypic susceptibility scores (GSS) were determined from the most recent genotypic resistance test available prior to the initiation of raltegravir. The main objective was to compare virologic results in patients who received raltegravir with a PI versus those who received raltegravir without a PI. Results: Four hundred forty-two subjects were evaluated from the respective sites in the EAP trial, of whom 340 were evaluable. The baseline mean HIV RNA was 4.6 log copies/ mL, and the mean CD4 cell count was 159 cells/μL. The median number of total and new antiretroviral agents in the background regimen was 4 and 2, respectively. Among the 254 patients who received a PI, the most common PI used was darunavir (89%). Etra-virine was commonly used in both groups: 39% of the PI group and 67% of the non-PI group. At week 12, 67% of PI patients and 64% of non-PI patients achieved HIV RNA <75 copies/mL and 85% and 86%, respectively, achieved HIV RNA <400 copies/mL GSS, which was similar in both groups at baseline, predicted achieving an HIV RNA of <400 and 75 copies/mL at week 12 (P < .05). Conclusions: In treatment-experienced patients, the combination of raltegravir with a regimen not containing a PI (used with etravirine in two-thirds of patients) had similar virologic activity when compared to more standard regimens using raltegravir with a PI. The main determinant of efficacy was the number of active drugs as measured by GSS. These data expand the potential utility of raltegravir in patients with multidrug-resistant HIV.