An experimental investigation of the effect of a justice violation on pain experience and expression among individuals with high and low just world beliefs.

BACKGROUND: Perceptions of injustice are linked with poorer physical and psychological outcomes in the context of pain and injury. Violations of injustice can arise out of violations of just world belief (JWB). However, no study has yet examined whether JWB moderates the effect of justice violation on pain experience. METHODS: The current study examined the effect of an experimental justice violation on acute pain outcomes and whether JWB moderated this effect. Participants completed the JWB scale and then engaged in two cold pressor tasks (CPT). Half the participants were told that the second CPT immersion was part of standard protocol; the other half were told that the painful procedure had to be repeated due to experimenter negligence. Participants provided report of pain intensity following each CPT immersion. Video records of participants undergoing the CPT were coded for presence and duration of pain behaviour. RESULTS: Exposure to the justice violation resulted in elevated pain intensity from the first to the second immersion only among participants with high JWB. For participants with low JWB and participants in the control condition, there was no significant difference in pain intensity across immersions. Control participants showed a decrease in pain behaviour from the first to the second immersion. In the negligence/ justice violation condition, reductions in pain behaviour were observed only among participants with low JWB. CONCLUSIONS: Our results indicate that individuals with high JWB may show particularly adverse reactions in response to justice violations in the context of acute pain experience.

North-South Corridor Demonstration Project: Ethical and Logistical Challenges in the Design of a Demonstration Study of Early Antiretroviral Treatment for Long Distance Truck Drivers along a Transport Corridor through South Africa, Zimbabwe, and Zambia.

Background. Long-distance truck drivers are at risk of acquiring and transmitting HIV and have suboptimal access to care. New HIV prevention strategies using antiretroviral drugs to reduce transmission risk (early antiretroviral therapy (ART) at CD4 count >350 cells/ µ L) have shown efficacy in clinical trials. Demonstration projects are needed to evaluate "real world" programme effectiveness. We present the protocol for a demonstration study to evaluate the feasibility, acceptability, and cost of an early ART intervention for HIV-positive truck drivers along a transport corridor across South Africa, Zimbabwe, and Zambia, as part of an enhanced strategy to improve treatment adherence and retention in care. Methods and Analysis. This demonstration study would follow an observational cohort of truck drivers receiving early treatment. Our mixed methods approach includes quantitative, qualitative, and economic analyses. Key ethical and logistical issues are discussed (i.e., choice of drug regimen, recruitment of participants, and monitoring of adherence, behavioural changes, and adverse events). Conclusion. Questions specific to the design of tailored early ART programmes are amenable to operational research approaches but present substantial ethical and logistical challenges. Addressing these in demonstration projects can inform policy decisions regarding strategies to reduce health inequalities in access to HIV prevention and treatment programmes.

The immunomodulatory nutritional intervention NR100157 reduced CD4+ T-cell decline and immune activation: a 1-year multicenter randomized controlled double-blind trial in HIV-infected persons not receiving antiretroviral therapy (The BITE Study).

BACKGROUND: The immunomodulatory nutritional product NR100157 was developed for human immunodeficiency virus (HIV)-infected individuals. We hypothesized that targeting the compromised gastrointestinal tract of HIV-infected individuals would result in systemic immunological benefits. METHODS: In a multicenter, randomized, controlled, double-blind trial, 340 HIV-1-positive adults not on antiretroviral therapy, with CD4(+) T-cell counts <800/µL, were given either NR100157 or an isocaloric and isonitrogenous control for 52 weeks. Primary outcome was CD4(+) T-cell count. Secondary outcomes included plasma viral load (pVL), safety, and tolerability. In a pilot study (n = 20), levels of CD4(+)CD25(+) and CD8(+)CD38(+) activation were measured (n = 20). The trial is registered at the Dutch Trial Register (NTR886) and ISRCTN81868024. RESULTS: At 52 weeks, CD4(+) T-cell decline showed a 40-cell/µL difference (P = .03) in the intention-to-treat population in favor of the immunomodulatory NR100157 (control vs active, -68 ± 15 vs -28 ± 16 cells/µL/year). The change in pVL from baseline was similar between groups (P = .81). In the pilot study, the percentage of CD4(+)CD25(+) was lower in the active group (P < .05) and correlated with changes in CD4(+) T-cell count (r = -0.55, P < .05). The percentage of CD8(+)CD38(+) levels was unaffected. CONCLUSIONS: The specific immunonutritional product NR100157 significantly reduces CD4(+) decline in HIV-1-infected individuals, and this is associated with decreased levels of CD4(+)CD25(+). (This nutritional intervention is likely to affect local gut integrity and gut-associated lymphoid tissue homeostasis, which in turn translates positively to systemic effects.) Clinical Trials Registration. ISRCTN81868024.

Earlier initiation of antiretroviral therapy, increased tuberculosis case finding and reduced mortality in a setting of improved HIV care: a retrospective cohort study.

OBJECTIVES: High early mortality after antiretroviral therapy (ART) initiation in resource-limited settings is associated with low baseline CD4 cell counts and a high burden of opportunistic infections. Our large urban HIV clinic in Uganda has made concerted efforts to initiate ART at higher CD4 cell counts and to improve diagnosis and care of patients coinfected with tuberculosis (TB). We sought to determine associated treatment outcomes. METHODS: Routinely collected data for all patients who initiated ART from 2005 to 2009 were analysed. Median baseline CD4 cell counts by year of ART initiation were compared using the Cuzick test for trend. Mortality and TB incidence rates in the first year of ART were computed. Hazard ratios (HRs) were calculated using multivariable Cox proportional hazards models. RESULTS: First-line ART was initiated in 7659 patients; 64% were women, and the mean age was 37 years (standard deviation 9 years). Median baseline CD4 counts increased from 2005 to 2009 [82 cells/µL (interquartile range (IQR) 24, 153) to 148 cells/µL (IQR 61, 197), respectively; P<0.001]. The mortality rate fell from 6.5/100 person-years at risk (PYAR) [95% confidence interval (CI) 5.5-7.6 PYAR] to 3.6/100 PYAR (95% CI 2.2-5.8 PYAR). TB incidence rates increased from 8.2/100 PYAR (95% CI 7.1-9.5 PYAR) to 15.6/100 PYAR (95% CI 12.4-19.7 PYAR). A later year of ART initiation was independently associated with decreased mortality (HR 0.91; 95% CI 0.83-1.00; P=0.04). CONCLUSIONS: Baseline CD4 cell counts have increased over time and are associated with decreased mortality. Additional reductions in mortality might be a result of a better standard of care and increased TB case finding. Further efforts to initiate ART earlier should be prioritized even in a setting of capped or reduced funding for ART programmes.

The Accelerating Access Initiative: experience with a multinational workplace programme in Africa.

PROBLEM: A multinational company with operations in several African countries was committed to offer antiretroviral treatment to its employees and their dependants. APPROACH: The Accelerating Access Initiative (AAI), an initiative of six pharmaceutical companies and five United Nations' agencies, offered the possibility of obtaining brand antiretroviral drugs (ARVs) at 10% of the commercial price. PharmAccess, a foundation aimed at removing barriers to AIDS treatment in Africa, helped to establish an HIV policy and treatment guidelines, and a workplace programme was rolled out from September 2001. LOCAL SETTING: Private sector employers in Africa are keen to take more responsibility in HIV prevention and AIDS care. An important hurdle for African employers remains the price and availability of ARVs. RELEVANT CHANGES: The programme encountered various hurdles, among them the need for multiple contracts with multiple companies, complex importation procedures, taxes levied on ARVs, lack of support from pharmaceutical companies in importation and transportation, slow delivery of the drugs, lack of institutional memory in pharmaceutical companies and government policies excluding the company from access to ARVs under the AAI. LESSONS LEARNED: The launch of the AAI enabled this multinational company to offer access to ARVs to its employees and dependants. The private sector should have access to these discounted drugs under the AAI. A network of local AAI offices should be created to assist in logistics of drugs ordering, purchase and clearance. No taxes should be levied on ARVs.

Database-supported teleconferencing: an additional clinical mentoring tool to assist a multinational company HIV/AIDS treatment program in Africa.

BACKGROUND: The lack of human resources for health is presently recognized as a major factor limiting scale-up of antiretroviral treatment (ART) programs in resourcelimited settings. The mobilization of public and private partners, the decentralization of care, and the training of non-HIV specialist nurses and general practitioners could help increase the number of HIV-infected patients receiving ART. In addition to other forms of training, scheduled teleconferences (TCs) have been organized to support a comprehensive HIV treatment program delivered by a private company's health team. OBJECTIVE: To describe the role of the TC as an additional tool in mentoring a company's health care workers (HCWs). METHOD: For this study, all TC reports were retrospectively reviewed and the questions classified by topic. Participating Heineken physicians evaluated the technical quality and scientific relevance of the TCs through an anonymous survey. RESULTS: From October 2001 to December 2003, 10 HCWs working in 14 operating companies in 5 African countries raised 268 problems during 45 TCs. A total of 79 questions (29%) were asked about antiretroviral (ARV) therapy, 53 (20%) about the diagnosis and treatment of opportunistic infection, 43 (16%) about ARV toxicity, 40 (15%) about care organization and policy, 32 (12%) about laboratory or drug supply, and 21 (8%) about biological parameters. The mean TC attendance rate was 70%. The level of satisfaction among local company physicians was 65% for logistics, 89% for scientific relevance, 84% for applicability of advice, and 85% overall. The most common complaints concerned the poor quality of the telephone connection and language problems for francophone participants. CONCLUSION: Database-supported teleconferencing could be an additional tool to mentor company HCWs in their routine care of HIV-infected workers and family members. The role and costeffectiveness of telemedicine in improving health outcomes should be further studied.

Plasma lipid concentrations after 1.5 years of exposure to nevirapine or efavirenz together with stavudine and lamivudine.

OBJECTIVES: To assess long-term changes in lipids and lipoproteins concentrations associated with exposure to non-nucleoside reverse transcriptase inhibitors. METHODS: Long-term analysis of plasma lipid concentrations was performed in patients starting first-line antiretroviral therapy with stavudine (d4T) and lamivudine, and either nevirapine or efavirenz. RESULTS: Concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides continued to increase, while high-density lipoprotein cholesterol showed a slight decrease compared with earlier reported increases after 48 weeks. CONCLUSIONS: Changes in body fat distribution expected to occur with continued exposure to d4T could offer a potential explanation for these findings.

[The use of the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz in the treatment of patients with a chronic HIV-I infection]. / Het gebruik van de niet-nucleoside-'reverse'-transcriptaseremmers nevirapine en efavirenz in de behandeling van patiënten met een chronische hiv I-infectie.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important group ofantiretroviral drugs in the treatment of a chronic HIV-I infection. The risk of viral resistance to NNRTIs is strongly diminished when they are used as part of a highly active antiretroviral combination therapy (HAART). Randomised trials have shown that nevirapine and efavirenz have a comparable antiretroviral efficacy. While rash and hepatotoxicity are associated with the use of nevirapine, the use of efavirenz is associated with neuropsychiatric abnormalities. The increase in HDL-cholesterol, which may be associated with a lower risk of cardiovascular disease, is greater with nevirapine than with efavirenz. The choice between the two drugs can be tailored to the needs of the patient. The rapid selection ofNNRTI-resistant HIV-I strains during the sub-optimal use of nevirapine and efavirenz demands the development of new NNRTIs.

Adequacy of peritoneal dialysis and the importance of preserving residual renal function.

The well-being and survival of dialysis patients not only depend on the removal of waste products and excess fluid, but also on the prevention of cardiovascular complications by maintaining normovolaemia and adequate blood pressure and avoidance of ectopic calcification. Also, the maintenance of nutritional status and adequate removal of middle molecules are amongst the most important issues in long-term renal replacement therapy. In this review, attention is given to optimal peritoneal small solute clearance and Kt/V and to the evidence concerning the role of residual renal function. In addition, factors that can influence this residual function are also discussed.

Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy.

Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).

Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naïve adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES).

BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naïve adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). RESULTS: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL) <50 copies/mL by intention-to treat analysis was 42.3%, 50.0%, and 56.5% for regimens A (n = 26), B (n = 22), and C (n = 23), respectively. The time to a pVL <50 copies/mL for the first time was significantly shorter in regimen C, and there was significantly more progression to CDC events in regimen B. These differences are possibly due to differences in baseline characteristics. Adverse events were lowest for regimen C; more signs associated with mitochondrial toxicity occurred in regimen A. Increase in CD4 count was comparable between arms. CONCLUSION: No statistically significant difference in efficacy was found between the two investigated once-daily dosed treatment regimens (B and C) and the reference (A). Regimen C possibly had a better virological response and less toxicity than regimens A and B.

Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009.

OBJECTIVE: Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity. METHODS: Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat. RESULTS: Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. CONCLUSIONS: IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.

Is there a difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child transmission of HIV in Africa?

BACKGROUND: Peripartum antiretroviral regimens have been shown to prevent mother-to-child transmission of HIV (MTCT) in randomized clinical trials; however, direct comparison of published results is impossible given methodological and population differences. OBJECTIVE: To directly compare the efficacy of different antiretroviral regimens in reducing the risk of 6-week MTCT rate in African breastfeeding populations. METHODS: Pooled analysis including all mother-infant pairs from any relevant trial: West African ZDV-placebo trials, Petra ZDV+3TC [two regimens A (pre/intra/post-partum) and B (intra/post-partum), placebo from Uganda and Tanzania], SAINT (NVP and Petra arm B), HIVNET012 (NVP, ultra short ZDV pp) and the Vitamin A trial (as placebo arm in South Africa). Peripartum HIV infection was any positive RNA or DNA polymerase chain reaction test < day 60. The MTCT risk was estimated at 6 weeks for each treatment arm and compared with placebo or single-dose NVP using logistic regression adjusting for maternal CD4 cell count, breastfeeding and birthweight. RESULTS: Overall, 4125 singleton live-births were included; 3629 (88%) were assessed for HIV status at 6 weeks of age. In comparison with placebo, zidovudine + lamivudine (ZDV+3TC) arm A [adjusted odds ratio (AOR), 0.23; P < 0.0001], ZDV+3TC arm B (AOR, 0.49; P < 0.001), antenatal ZDV short (AOR, 0.55; P = 0.006) and nevirapine (NVP) (AOR, 0.60; P = 0.0007) significantly reduced MTCT. In comparison with NVP, only the longest regimen of ZDV+3TC (AOR, 0.39, P < 0.0005) was significantly more effective. CONCLUSION: These results are in line with current World Health Organisation guidelines suggesting equivalence of choice between single-dose NVP and short-course ZDV, and confirm the greater efficacy of ZDV+3TC than with any single antiretroviral drug.

The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART.

BACKGROUND: A substantial number of patients start their first-line antiretroviral therapy at an advanced stage of an HIV-1 infection. Potential differences between specific drug regimens in antiviral efficacy and safety in these patients are of major importance. METHODS: A post-hoc analysis within the randomized controlled 2NN trial comparing efficacy between regimes containing nevirapine (NVP), efavirenz (EFV), or both, in addition to stavudine and lamivudine. PRIMARY OUTCOME: risk of virologic failure in different strata of baseline CD4 T-lymphocyte counts and plasma HIV-1 RNA concentrations (pVL). Virologic failure: never reaching a pVL < 400 copies/ml, or a rebound to two consecutive values > 400 copies/ml. RESULTS: The risk of virologic failure was increased at very low CD4 counts (< 25 x 10(6) cells/l) compared to CD4 counts > 200 x 10(6) cells/l [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.93-1.77]. The same was seen for a pVL > or = 100,000 copies/ml compared to a lower pVL (HR, 1.20; CI, 0.96-1.50). There were no statistically significant differences between NVP and EFV in risk of virologic failure within any of the CD4 or pVL strata, although EFV performed slightly better in the low CD4 stratum. The incidence of rash in the NVP group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the EFV group were not associated with CD4 cell count. CONCLUSIONS: Initial antiretroviral therapy including NVP or EFV is effective in patients with an advanced HIV-1 infection. A high baseline CD4 cell count is associated with the occurrence of rash in female patients using NVP.

Occult hepatitis B virus infection before and 1 year after start of HAART in HIV type 1-positive patients.

Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies and HBV-DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. The clinical relevance of this phenomenon in HIV-1 patients starting highly active antiretroviral therapy (HAART) is unknown. We followed 93 therapy naive HIV-1-infected adults who were anti-HBc positive, HBsAg and HBeAg negative, during first year of HAART. At baseline, HBV-DNA was quantified, and HBV genotype was determined in the HBV-DNA-positive patients by sequencing a part of the HBV genome. Four of 93 patients (4%) were HBV DNA positive at baseline. All four patients tested negative for HBV-DNA after 1 year. They all received lamivudine as part of their HAART. They had no clinically significant liver enzyme elevations (LEE) during the first year of HAART. Two of the patients had a genotype A, one genotype E, and in the fourth patient sequencing was not possible. In one patient we found significant mutations in the a determinant region of HBsAg, at positions 142 and 144. In our population of therapy-naive HIV-1-infected adults who were anti-HBc positive, we found occult HBV infection in 4% of the patients. We did not find an increased risk for LEE in our population of patients after the start of HAART. Our results illustrate that occult HBV infection is more a diagnostic than a clinical problem. It may be caused by very low levels of HBV replication, concurrent presence of HBsAg and anti-HBs, or mutations in the HBsAg a determinant.

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study.

BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy.

OBJECTIVES: To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based first-line highly active antiretroviral therapy (HAART). DESIGN AND METHODS: A retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive patients initiating either PI-based or NVP-based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason. RESULTS: In total, 920 and 109 patients initiated PI- and NVP-based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/microL in the NVP group) and had higher median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/microL in the PI group and 212 cells/microL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/microL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes. CONCLUSION: Patients successfully treated with NVP-based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI-based HAART.

Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors.

BACKGROUND: Most toxicities associated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) are thought to result from mitochondrial toxicity. These toxicities include peripheral neuropathy, pancreatitis, lactic acidosis, and peripheral lipoatrophy. Unfortunately, there are no validated laboratory markers for clinically assessing, let alone predicting, the onset of mitochondrial toxicity associated with NRTI therapy. OBJECTIVES: To provide preliminary evidence of the potential clinical utility of an assay which has been developed for quantifying mitochondrial DNA (mtDNA) in clinical samples from HIV-infected patients. METHODS: A single-tube duplex real-time DNA-nucleic acid sequence-based amplification (NASBA) assay (Mitox, Primagen, Amsterdam, the Netherlands) was used to quantify mtDNA in cryopreserved peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients during their prior participation in a randomized placebo-controlled trial comparing zidovudine (ZDV) monotherapy with combinations of ZDV plus either dideoxycytidine (ddC) or didanosine (ddI) (the Delta trial). Patients were antiretroviral naïve prior to entering the trial. Samples obtained during the initial 48 weeks of treatment were tested. RESULTS: A significant decline of mtDNA, both in an intent-to-treat and in an as-treated analysis, was observed in patients treated with ZDV+ddC and ZDV+ddI, but not with ZDV alone, consistent with the results expected from the degree of mtDNA depletion described for each of these drugs in vitro. CONCLUSIONS: This single-tube duplex real-time DNA-NASBA assay was shown to measure mtDNA accurately in PBMC. Treatment with a combination of two NRTIs was associated with greater reductions in mtDNA than obtained for ZDV monotherapy. The relevance of these results in predicting treatment toxicity requires further evaluation.

Antiretroviral therapy in previously untreated adults infected with the human immunodeficiency virus type I: established and potential determinants of virological outcome.

The aim of highly active antiretroviral therapy (HAART) for patients chronically infected with the human immunodeficiency virus type I is to achieve maximal and durable viral suppression. Maintaining the blood plasma HIV-I-RNA concentration (pVL) <50 copies/ml is currently considered appropriate for this goal. With the current treatment options, the percentage of previously untreated patients who achieve a pVL <50 copies/ml after one year of initial HAART is about 70%. Characteristics of the host, virus, drugs and the treatment team have been associated with the virological response to initial HAART. Adjusting the initial HAART regimen and patient management to a risk profile based on these factors is possibly helpful in improving the virological response to HAART. Adherence to a potent and well-tolerated HAART regimen is likely to be the most relevant factor for virological success. The additive value of the other factors needs to be clarified.