Standard-dose efavirenz vs. standard-dose nevirapine in antiretroviral regimens among HIV-1 and tuberculosis co-infected patients who received rifampicin

Background

There is limited comparative data between efavirenz (EFV) 600 mg/day and nevirapine (NVP) 400 mg/day‐based antiretroviral therapy (ART) among HIV‐1 patients with tuberculosis (TB) and receiving rifampicin.

Methods

A retrospective cohort study was conducted in all ART‐naïve patients who were receiving rifampicin between January 2002 and December 2005.

Results

Of 188 patients, 77 and 111 patients were initiated on EFV‐based ART (EFV group) and NVP‐based ART (NVP group), respectively. Overall, median [interquartile range (IQR)] CD4 count was 36 (15–77) cells/μL and median (IQR) viral load was 5.6 (5.2–5.9) HIV‐1 RNA log copies/mL. At 48 weeks, 77.9% (60/77) in the EFV group and 67.6% (75/111) in the NVP group achieved HIV‐1 RNA <50 copies/mL (P=0.140, odds ratio =0.590, 95% confidence interval=0.302–1.153). At 24 and 48 weeks, respective median CD4 counts were 174 and 254 cells/μL in the EFV group and 156 and 218 cells/μL in the NVP group (P>0.05). By binary logistic regression, treatment group was not associated with HIV‐1 RNA <50 copies/mL (P>0.05). No patient in the EFV group and eight (7.2%) patients in the NVP group discontinued ART because of adverse reactions (P=0.084).

Conclusions

For HIV–TB co‐infected patients who receive rifampicin, efficacy of 600 mg EFV‐based and 400 mg NVP‐based ART may be similar, although adverse events tend to be higher in NVP‐based ART.     

Detecting impaired glucose tolerance or type 2 diabetes mellitus by means of an oral glucose tolerance test in HIV‐infected patients

Objective

As a proactive diagnosis of diabetes mellitus (DM) may prevent the onset of severe complications, we used an oral glucose tolerance test (OGTT) to check for impaired glucose tolerance (IGT) and DM in patients with long‐standing HIV infection and long durations of exposure to antiretroviral drugs with normal fasting plasma glucose (FPG) levels.

Methods

This was a cross‐sectional, single‐centre study. The homeostatic model assessment for insulin resistance (HOMA‐IR) and 2‐h post‐load glucose levels were used to evaluate patients with known HIV‐1 infection since before 1988 and no previous diagnosis of DM for whom data on hepatitis C virus (HCV) and hepatitis B virus (HBV) infection were available.

Results

Eighty‐four Caucasian patients [67 (80%) male; median age 45.7 years; range 43.8–49.1 years] were able to be evaluated; 65 (77%) were coinfected with HCV, and seven (8%) were coinfected with HBV. Median (interquartile range [IQR]) exposure to antiretrovirals was 12.8 (10.4–16.5) years. Fifteen patients (18%) had a previous AIDS‐defining event, 64 (76%) had HIV RNA<50 copies/mL, and the median (IQR) CD4 count was 502 (327–628) cells/μL. The median [IQR] FPG was 81 mg/dL (4.5 mmol/L) [75–87 mg/dL (4.2–4.8 mmol/L)], and the median (IQR) HOMA‐IR was 2.82 (1.89–4.02). After OGTT, nine patients (11%) were diagnosed as having IGT (6) or DM (3). A first multivariable analysis showed that CD4 cell count (P=0.038) and HOMA‐IR (P=0.035) were associated with IGT or DM, but a second model including only the variables with a P‐value of <0.2 in the univariable analysis (CD4 cell count, HBV coinfection, and HOMA‐IR) found that only HOMA‐IR independently predicted IGT or DM.

Conclusions

In patients with long‐standing HIV infection and normal FPG levels, an OGTT can reveal IGT or DM.     

Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months

Objective

To quantify HIV‐RNA in plasma, in lymphoid tissue and proviral DNA in peripheral blood mononuclear cells and to relate these to immunological markers among patients with plasma viral load counts of ≤ 200 HIV‐RNA copies/mL.

Methods

A prospective study of one hundred and three patients was undertaken with an inclusion criteria of plasma viral load of ≤ 200 copies/mL. The patients had advanced HIV infection; 25% had developed AIDS. Patients were seen every 6 months for a period of 2 years.

Results

The median plasma viral load was < 20 copies/mL with no increase during follow‐up. Thirty‐one per cent had plasma viral load of ≤ 20 copies/mL at all visits, 44% had ≥ 1 measurement with 21–200 and 25% had ≥ 1 sample with plasma HIV‐RNA > 200 copies/mL. Lymphoid tissue viral load was low at enrolment and declined further during follow‐up. Baseline HIV‐DNA and immunoglobulin (IgA) differed significantly between the plasma viral load rebound groups (P < 0.05).

Conclusion

In this cohort, selected solely on the basis of having a plasma viral load of ≤ 200 copies/mL, we found stable or declining viral loads in the measured compartments during 2 years of follow‐up. Baseline HIV‐DNA and IgA levels were higher among patients with less complete virological suppression relative to patients with persistently undetectable plasma HIV‐RNA. Hence, a high cellular level of HIV‐DNA and high plasma IgA may predict subsequent development of low‐grade viraemia.

     

Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort

Objectives

Tenofovir disoproxil fumarate (TDF) is active against hepatitis B virus (HBV) and HIV. However, the long‐term efficacy of tenofovir disoproxil fumarate (TDF) is not well known and the appearance of resistance is a major concern. We have studied the efficacy of TDF against HBV in patients treated at an Infectious Diseases Unit.

Methods

We carried out a retrospective observational study of the efficacy of TDF against HBV replication in a cohort of 52 HIV‐coinfected patients who received TDF for at least 6 months.

Results

The median duration of follow‐up of TDF treatment was 34 months. Forty‐one patients (79%) were positive for HBV envelope antigen (HBeAg) and 35 had received previous lamivudine monotherapy for a median duration of 32 months. Virological breakthrough was observed in nine cases (17%). At the end of the follow‐up period, HBV DNA levels were <1000 copies/mL in 42 patients (81%) and <200 copies/mL in 31 patients (60%). There were no significant differences between the lamivudine‐naïve and lamivudine‐experienced groups. In the lamivudine‐experienced group, the duration of previous lamivudine monotherapy was associated with failure to achieve HBV DNA levels <200 copies/mL (P=0.036). Adding lamivudine or emtricitabine to TDF did not improve virological suppression. In 39 patients who achieved <200 HBV DNA copies/mL during TDF treatment, virological breakthrough was seen only in two patients (5%) after a median follow‐up duration of 39.7 months.

Conclusions

TDF was able to control HBV replication in most HIV‐coinfected patients after a median follow‐up duration of 34 months, regardless of previous lamivudine treatment. However, a sizeable proportion of patients developed virological breakthrough.     

Risk of high‐level viraemia in HIV‐infected patients on successful antiretroviral treatment for more than 6 months

Objectives

According to the Swiss Federal Commission for HIV/AIDS, HIV‐infected patients on successful antiretroviral treatment have a negligible risk of transmitting HIV sexually. We estimated the risk that patients considered to have an undetectable viral load (VL) are actually viraemic.

Methods

A Danish, population‐based nationwide cohort study of HIV‐infected patients with VL <51 HIV‐1 RNA copies/mL for more than 6 months was carried out for the study period 2000–2008. The observation time was calculated from 6 months after the first VL <51 copies/mL to the last measurement of VL or the first VL >50 copies/mL. The time at risk of transmitting HIV sexually was calculated as 50% of the time from the last VL <51 copies/mL to the subsequent VL if it was >1000 copies/mL. The outcome was the time at risk of transmitting HIV sexually divided by the observation time.

Results

We identified 2680 study subjects contributing 9347.7 years of observation time and 56.4 years of risk of transmitting HIV (VL>1000 copies/mL). In 0.6% [95% confidence interval (CI) 0.5–0.8%] of the overall observation time the patients had VL >1000 copies/mL. In the first 6 months this risk was substantially higher (7.9%; 95% CI 4.5–11.0%), but thereafter decreased and was almost negligible after 5 years (0.03%; 95% CI 0.0–0.2%). The risk was higher in injecting drug users, but otherwise did not differ between subgroups of patients.

Conclusion

The risk of viraemia and therefore the risk of transmitting HIV sexually are high in the first 12 months of successful antiretroviral treatment, but thereafter are low.     

Effectiveness and tolerability of a once-daily amprenavir/ritonavir-containing highly active antiretroviral therapy regimen in antiretroviral-naïve patients at risk for nonadherence: 48-week results after 24 weeks of directly observed therapy

Objectives

To determine the safety and effectiveness of a once‐daily highly active antiretroviral therapy (HAART) regimen in patients at risk for poor adherence using directly observed therapy (DOT) for 24 weeks followed by weekly phone contact for another 24 weeks.

Methods

A prospective, open‐label pilot study was carried out. Antiretroviral‐naïve patients with advanced HIV disease were treated with once‐daily amprenavir 1200 mg, ritonavir 200 mg, didanosine 400 mg and lamivudine 300 mg. After 24 weeks, DOT was substituted by weekly phone contact. Measurements of viral load and CD4 cell count, and safety laboratory measurements, were taken regularly for 48 weeks.

Results

Twenty‐two patients were enrolled in the study, of whom 19 completed at least 4 weeks of treatment. Seventeen patients completed 24 weeks and 13 completed 48 weeks. None discontinued treatment as a result of adverse events. The median baseline HIV viral load was 5.29 log₁₀ HIV‐1 RNA copies/mL and the median CD4 cell count was 20 cells/μL. At weeks 24 and 48, 74% of the patients had viral loads <400 copies/mL. At 48 weeks, the median decrease in viral load from baseline was 3.06 log₁₀ copies/mL, and the median increase in CD4 cell count was 118 cells/μL. The median trough plasma amprenavir concentrations at weeks 1 and 24 were 1.87 and 1.42 μg/mL, respectively.

Conclusions

This study suggests that DOT followed by weekly patient contact results in good treatment outcome in this challenging population. The median trough plasma amprenavir concentrations were above the effective concentration of drug that resulted in 90% inhibition of viral load in vivo (EC₉₀) for wild‐type HIV.

     

Performance of a World Health Organization first-line regimen (stavudine/lamivudine/nevirapine) in antiretroviral-naïve individuals in a Western setting

Objectives

In 2003, the World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) introduced the ‘3 by 5 Initiative’ to treat 3 million individuals by the end of 2005. This study evaluates the time to treatment termination, viral load suppression, and detection of drug resistance among antiretroviral‐naïve individuals initiating stavudine/lamivudine/nevirapine (d4T/3TC/NVP) in British Columbia, Canada, to provide a context for future programme planning.

Methods

Primary outcome was time to treatment termination. Secondary outcome was time to viral suppression. Accumulation of drug resistance mutations was followed systematically in the first 145 individuals over 30 months. Cox proportional hazard regression identified factors associated with termination and suppression.

Results

312 antiretroviral‐naïve individuals initiated d4T/3TC/NVP between August 1996 and September 2003. Median follow‐up time was 26.5 months (interquartile range [IQR] 6.8–46.5). At a median of 12.4 months (IQR 4.3–33.3), 132 (42.3%) patients switched treatment, 53 (17.0%) stopped therapy and 26 (8.3%) died. Of 308 subjects with baseline viral load >500 copies/mL, 223 (72.4%) suppressed to ≤500 copies/mL at a median of 2.0 months. Among 145 (46.5%) individuals followed longitudinally, resistance mutations to NNRTI, 3TC, or other NRTI were detected in 11 (7.6%), six (4.1%) and four (2.8%) individuals after 12 months of therapy; and in 23 (15.9%), 17 (12.0%), and six (4.1%) individuals after 30 months.

Conclusions

The population requiring second‐line treatment was 30% at 12 months and 40% at 24 months; 20% had detectable drug resistance mutations by 30 months. While these results are from a Western setting, they illustrate the need to consider second‐ and third‐line approaches as antiretroviral treatment scale‐up continues in the developing world.

     

Long‐term (96‐week) follow‐up of antiretroviral‐naïve HIV‐infected patients treated with first‐line lopinavir/ritonavir monotherapy in the MONARK trial*

Background

The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral‐naïve patients.

Methods

A total of 136 antiretroviral‐naïve patients, with a CD4 cell count above 100 cells/μL and a plasma HIV RNA below 100 000 HIV‐1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n=83) or lopinavir/ritonavir+zidovudine/lamivudine (n=53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent‐to‐treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n=83), and then focused on patients who had an HIV RNA <50 copies/mL at week 48 (n=56).

Results

At week 96, 39 of 83 patients (47%) had HIV RNA <50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA >400 copies/mL. Focusing on the 56 patients with an HIV RNA <50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA <50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI‐associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96.

Conclusion

By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA <50 copies/mL at week 96. The occurrence in some patients of low‐level viraemia (50–500 copies/mL) may increase the risk of drug resistance. First‐line lopinavir/ritonavir monotherapy cannot be systematically recommended.     

Mother-to-child transmission of HIV-1: association with malaria prevention, anaemia and placental malaria

Objectives

Malaria infection may impact on mother‐to‐child transmission (MTCT) of HIV‐1. Prevention of malaria in pregnancy could thus potentially affect MTCT of HIV. We studied the impact of intermittent preventive treatment during pregnancy (IPTp) on HIV‐1 MTCT in southern Mozambique.

Methods

A total of 207 HIV‐positive Mozambican pregnant women were enrolled in the study as part of a randomized placebo‐controlled trial of two‐dose sulfadoxine‐pyrimethamine (SP) IPTp in women receiving single‐dose nevirapine to prevent MTCT of HIV. HIV RNA viral load, maternal anaemia and peripheral and placental malaria were assessed at delivery. Infant HIV status was determined by DNA polymerase chain reaction (PCR) at 1 month of age.

Results

There were 19 transmissions of HIV in 153 mother–infant pairs. IPTp with SP did not have a significant impact on MTCT (11.8% in the SP group vs. 13.2% in the placebo group; P=0.784) or on maternal HIV RNA viral load [16 312 (interquartile range {IQR} 4076–69 296) HIV‐1 RNA copies/mL in the SP group vs. 18 274 (IQR 5471–74 104) copies/mL in the placebo group; P=0.715]. In multivariate analysis, maternal HIV RNA viral load [adjusted odds ratio (AOR) 19.9; 95% confidence interval (CI) 2.3–172; P=0.006] and anaemia (haematocrit <33%; AOR 7.5; 95% CI 1.7–32.4; P=0.007) were independent risk factors for MTCT. Placental malaria was associated with a decrease in MTCT (AOR 0.23; 95% CI 0.06–0.89; P=0.034).

Conclusions

IPTp with SP was not associated with a significant impact on MTCT of HIV. Maternal anaemia was an independent risk factor for MTCT.     

Effect of food on the antiviral activity of didanosine enteric-coated capsules: a pilot comparative study

Objectives

To determine the effect of food on the antiviral activity of enteric‐coated (EC) capsules of didanosine (ddI).

Methods

We conducted a pilot, randomized, open‐label study of 28‐day ddI‐EC capsules monotherapy‐administered in a fasted state (group 1, n=11) or with food (group 2, n=10) to treatment‐naïve chronically HIV‐1‐infected individuals. To assess the antiviral efficacy, HIV‐1 RNA was determined at baseline, day 3, day 7 and weekly thereafter. The area under the HIV‐1 RNA curve minus baseline weighted by time (AUCMB/day) was calculated.

Results

Mean baseline HIV‐1 RNA was 4.2 log₁₀ copies/mL in group 1 and 3.8 log₁₀ copies/mL in group 2. After 28 days, the mean HIV‐1 RNA reduction was 0.99 log₁₀ copies/mL [95% confidence interval (CI) 0.45–1.53] for group 1 and 0.89 log₁₀ copies/mL (95% CI 0.38–1.40) for group 2. AUCMB/day values were 0.775 log₁₀ copies/mL (95% CI 0.33–1.22) and 0.774 log₁₀ copies/mL (95% CI 0.48–1.07), respectively, showing no difference in the rate of decrease of HIV‐1 RNA (P=0.995). Mean ddI plasma levels at day 28 were 0.0234 mg/L for group 1 and 0.0227 mg/L for group 2 (P=0.96).

Conclusions

In this pilot study, the administration of food did not have any significant effect on the antiviral activity of ddI‐EC capsules.     

Secure antiretroviral therapy delivery in a resource-limited setting: streamlined to minimize drug resistance and expense

Background

We report the design and analysis of a streamlined approach to the delivery of antiretroviral therapy (ART) that minimized risk for emergence of ART drug resistance (ART‐DR) in a resource‐limited setting.

Methods

The algorithm of care for persons with HIV comprised generic, fixed‐dose, twice‐daily stavudine, lamivudine and nevirapine (GPO‐VIR), scheduled and unannounced pill counts and measurement of viral load at months 6 and 18 after initiation of ART. We evaluated adherence as measured by pill counts, HIV suppression and programmatic costs.

Results

Over a 4‐year period, 214 of 330 patients (64.8%) were enrolled; baseline median CD4 count was 84 cells/μL. At month 1, nine patients (4.2%) discontinued GPO‐VIR because of skin rash. At month 6, 199 patients (93%) achieved viral load ≤400 HIV‐1 RNA copies/mL, with current alcohol use the sole predictor of treatment failure [adjusted Relative Risk (aRR)=1.67; 95% confidence interval=1.05–2.48; P<0.001]. Most patients (97%) with HIV suppression at month 6 had viral loads ≤50 copies/mL at month 18; all had ≥75% visit compliance and 192 (98%) had ≥75% adherence measured by pill counts. The estimated annual costs were $111.92 per patient for the pill counts, home visits and viral load measurement.

Conclusions

Secure ART delivery, while minimizing risk for non‐adherence and ART‐DR, is clinically and economically feasible in this resource‐limited setting.     

Nevirapine- versus efavirenz-based highly active antiretroviral therapy regimens in antiretroviral-naïve patients with advanced HIV infection

Objective

To compare virological and immunological responses to nevirapine (NVP)‐based and efavirenz (EFV)‐based highly active antiretroviral therapy (HAART) regimens in antiretroviral‐naïve patients with advanced HIV infection.

Methods

A retrospective observational cohort study was conducted on antiretroviral‐naïve HIV‐infected patients whose pretreatment CD4 cell counts were less than 100 cells/μL or whose viral loads were greater than 100 000 HIV‐1 RNA copies/mL.

Results

Baseline characteristics of patients in the NVP (n=24) and EFV (n=29) groups were not different. The proportion of patients with viral loads >100 000 copies/mL was higher in the EFV group. The probability of virological success estimated by the Kaplan‐Meier method showed that 3‐ and 6‐month success rates were 30.8% [95% confidence interval (CI): 16.7–52.2%] and 63.1% (95% CI: 44.7–81.3%) for the NVP group. The corresponding values were 41.2% (95% CI: 25.8–61.0%) and 62.9% (95% CI: 45.7–80.1%) for the EFV‐based group. The median success times of the two groups were about 4 and 3 months (P=0.678), respectively, for NVP and EFV. Cox's proportional hazard was used after adjusting for age, previous opportunistic infections (OIs), and viral load at baseline, and showed that patients who received the NVP‐based regimen had about 25% [hazard ratio (HR)=0.75, 95% CI: 0.37–1.51] less chance of virological success than patients who received the EFV‐based regimen (P=0.415). The median times to CD4≥100 cells/μL were 5.6 and 4.4 months for the NVP‐ and EFV‐based regimens, respectively (log‐rank test, P=0.144).

Conclusions

NVP‐ and EFV‐based HAART regimens as initial regimens in patients with advanced HIV infection are effective and comparable, in term of virological and immunological responses. However, further large‐scale randomized controlled clinical trials in this group of patients with advanced HIV infection are needed.

     

Vertically acquired HIV diagnosed in adolescence and early adulthood in the United Kingdom and Ireland: findings from national surveillance

Objective

The aim of the study was to describe the characteristics of young people with vertically acquired HIV diagnosed aged ≥13 years.

Methods

A retrospective review of HIV diagnoses reported to well‐established national paediatric and adult HIV surveillance systems in the United Kingdom/Ireland was conducted.

Results

Forty‐two young people with vertically acquired HIV diagnosed aged ≥13 years were identified; 23 (55%) were female, 40 (95%) were black African and 36 (86%) were born in sub‐Saharan Africa. The median age at HIV diagnosis was 14 years (range, 13–20 years). Half of the patients presented with symptoms; the remainder were screened for HIV following diagnosis of a relative. The median CD4 count at diagnosis was 210 cells/μL (range, 0–689 cells/μL), 12 patients (29%) were diagnosed with AIDS at HIV diagnosis or subsequently, and 34 (81%) started combination antiretroviral therapy (ART), most (31 of 34) within a year of diagnosis.

Conclusion

A small number of young people with vertically acquired HIV survive childhood without ART and are diagnosed at age ≥13 years in the United Kingdom/Ireland. Half of the patients were asymptomatic, highlighting the importance of considering HIV testing for all offspring of HIV‐infected women, regardless of age or symptoms. Increased awareness among clinicians and parents is required to reduce delayed presentation with advanced disease and to avoid onward transmission as these young people become sexually active.