South Africa’s national antiretroviral (ARV) treatment program expanded in 2010 to include the nucleoside reverse transcriptase (RT) inhibitors (NRTI) tenofovir (TDF) for adults and abacavir (ABC) for children. We investigated the associated changes in genotypic drug resistance patterns in patients with first-line ARV treatment failure since the introduction of these drugs, and protease inhibitor (PI) resistance patterns in patients who received ritonavir-boosted lopinavir (LPV/r)-containing therapy.We analysed ARV treatment histories and HIV-1 RT and protease mutations in plasma samples submitted to the Tygerberg Academic Hospital National Health Service Laboratory.Between 2006 and 2012, 1,667 plasma samples from 1,416 ARV-treated patients, including 588 children and infants, were submitted for genotypic resistance testing. Compared with 720 recipients of a d4T or AZT-containing first-line regimen, the 153 recipients of a TDF-containing first-line regimen were more likely to have the RT mutations K65R , Y115F , L74VI , and K70EGQ (7.8% vs. 0.4%) and recipients of an ABC-containing first-line regimen were more likely to have K65R , Y115F , and L74VI . Among the 490 LPV/r recipients, 55 (11%) had ≥1 LPV-resistance mutations including 45 (9.6%) with intermediate or high-level LPV resistance. Low (20 patients) and intermediate (3 patients) darunavir (DRV) cross resistance was present in 23 (4.6%) patients.Among patients experiencing virological failure on a first-line regimen containing two NRTI plus one NNRTI, the use of TDF in adults and ABC in children was associated with an increase in four major non- thymidine analogue mutations. In a minority of patients, LPV/r-use was associated with intermediate or high-level LPV resistance with predominantly low-level DRV cross-resistance. The South African National Government began providing antiretroviral (ARV) therapy to the public sector in 2004. Until 2009, standard first-line regimens were stavudine (d4T) plus lamivudine (3TC) combined with a third agent: a non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) in adults and older children or ritonavir-boosted lopinavir (LPV/r) in young children who had received nevirapine (NVP) for prevention of mother-to-child transmission (PMTCT). In 2010, when the South African guidelines were aligned to updated World Health Organization guidelines, D4T was replaced by tenofovir disoproxil fumarate (TDF) in adults and older children and abacavir (ABC) in younger children, respectively. Adults beginning ARV treatment increasingly received TDF rather than d4T for first-line therapy and children increasingly received ABC rather than d4T Since 2006, the National Health Laboratory Service (NHLS) virology laboratory at Tygerberg Academic Hospital has provided ARV genotypic resistance testing for public sector clinics in the Western Cape, Gauteng and Eastern Cape provinces, as allowed by individual clinic or hospital budgets or external funding. Samples received between 2006 and 2012 from children (age below 15 years) and adults with virological failure on a standard first- or second-line regimen for whom demographic and ARV treatment information were provided by their physicians were included in the study. The Stellenbosch University Health Research Ethics Committee approved the study, reference number: N11/09/274.The treatment histories provided by physicians were assessed in light of the contemporaneous ARV treatment policies in South Africa. Until 2010, the standard adult first-line regimens were d4T combined with 3TC plus either NVP or efavirenz (EFV). Zidovudine (AZT) was often used as a substitute for d4T in case of toxicity. Children younger than three years were generally treated with a boosted lopinavir (LPV/r)-containing first-line regimen under the assumption that a high proportion had been infected with a virus exposed to NNRTI selection pressure as a result of maternal NVP therapy. Initially standard second-line therapy for adults consisted of AZT combined with didanosine (DDI) and LPV/r In accordance with the revised recommendations, TDF or ABC replaced d4T in a number of patients, who experienced adverse effects, but this was not always noted; therefore a subset of patients recorded as receiving TDF or ABC in combination with 3TC and either NVP or EFV may have previously received d4T.Laboratory monitoring and detection of failure: The recommended frequency of viral load testing and CD4 testing after initiation of ARV therapy, was six monthly, until the testing frequency was reduced, in 2010, to testing after six months, 12 months and then annually. The definition of virologic failure in adults and adolescents, according to the original South African National Guidelines was repeated HIV viral load measures above 5000 copies/ml. Virological failure in children was defined as rebound of viral load to baseline, and switching to a second-line paediatric regimen was otherwise based on clinical and immunological failure http://hivdb.stanford.edu/pages/webservices). HIV-1 subtyping was performed using the Rega Subtyping Tool Standard dideoxynucleotide terminator sequencing was performed using an in-house protocol The following non-polymorphic ARV-selected mutations were classified as drug resistance mutations (DRM): (i) the NRTI resistance mutations M41L, A62V, K65RN, D67NG, T69D, T69 insertions, T69 deletion, K70REGQ, L74VI, V75MT, F77L, Y115F, F116Y, Q151M, M184VI, L210W, T215YFSDCIV, and K219QENR; (ii) the NNRTI resistance mutations A98G, L100I, K101EPH, K103NS, V106MA, E138KGQ, V179DEFT, Y181CIV, Y188LCH, G190ASEQ, H221Y, P225H, F227LC, M230L, and K238T; and (iii) the PI resistance mutations L10F, V11I, L23I, L24I, D30N, L33F, M46IL, I47VA, G48VM, I50V, I54VMLATS, G73STCA, T74P, L76V, V82ATFSCML, I84V, N88DS, L89V, L90M.Different RT mutations at the same residue were pooled, including the NRTI-resistance mutations D67NG, K70EGQ, L74VI, M184VI, T215YF, K219QE and the NNRTI-resistance mutations K101EH, K103NS, Y188LCH, and G190ASEQ. Thymidine analogue mutations (TAMs) were defined as M41L, D67NG, K70R, L210W, T215YF, and K219QE. The Q151M complex of mutations was defined as Q151M alone or in combination with one or more of the following mutations: A62V, V75I, F77L, and F116Y. Sequences that terminated between positions 219 and 229 were included in the analysis of NRTI mutation frequency but not in the analysis of NNRTI mutation frequency. The following protease mutations were considered LPV/r-resistance mutations: L10F, L24I, V32I, L33F, M46IL, I47A, I50V, I54MLV, L76V, V82ATSFMC, I84V, L89V, L90M.When more than one sample was received while a patient received a particular regimen, the sample containing the most drug resistance was chosen, which equalled the cumulative resistance in almost all cases.We used the Fisher Exact statistic to compare the proportions of NRTI- and NNRTI-resistance proportions in patients receiving different first-line regimens. Although no explicit correction for multiple comparisons was made, only those differences with a p-value <0.01 were noted.Overall, 1,515 patients had samples submitted for HIV-1 genotypic resistance testing between May 2006 and July 2012. Ninety-four percent  of patients had a physician-provided ARV treatment history consistent with a standard first- or second-line regimen. Two hundred patients had more than one sample submitted for genotypic resistance testing, including 147 patients who had samples obtained while on different ARV treatment regimens.TDF use in adults increased from 3% between 2006 and 2009 to 37% between 2010 and 2012 and ABC use from 2% to 6%. In children, ABC use increased from 13% between 2006 and 2009 to 29% between 2010 and 2012. The increase in TDF and ABC use was associated with a concurrent decrease in d4T, DDI and AZT use. Overall, in both age groups, d4T, AZT, and DDI had been used in 65%, 32%, and 20% of patients between 2006 and 2009 and in 45%, 26%, and 14% of patients between 2010 and 2012.Among the 569 adults receiving first-line regimens 313 (55%) received d4T plus 3TC, 90 (16%) AZT plus 3TC, 153 (27%) TDF plus 3TC, 13 (2%) received ABC plus 3TC. Four hundred and ninety five (87%) received EFV and 74 (13%) NVP. Among the 508 children and infants receiving first-line therapy, 421 (83%) received D4T and 3TC, 65 (13%) ABC plus 3TC and 22 (4%) received AZT plus 3TC. Three hundred and forty one (67%) received EFV, 150 (30%) received LPV/r and 17 (3%) received NVP. Among the 290 adults receiving second-line regimens, the most commonly used regimens included: 126 (43%) receiving AZT plus DDI, 43 (15%) receiving AZT plus 3TC, 37 (13%) receiving TDF plus 3TC/FTC, and 68 (23%) receiving three or more NRTIs, with the rest receiving rare combinations, in each case combined with LPV/r. A wide variety of second-line regimens were used in children and infants, due to the need of expert advice before changing the regimen.HIV-1 subtype C sequences comprised 98.2% of patient sequences. The remaining virus subtypes included A (0.9%), B (0.1%), BC recombinants (0.6%) and miscellaneous subtypes and recombinant forms (0.2%). The median uncorrected genetic distance (Hamming distance) for sequences from different patients was 7.4%  patients failing ARV and receiving TDF and in 9/54 (16.7%) patients receiving ABC compared with 20/720 (2.8%) patients receiving d4T or AZT (p<0.001 for both TDF and ABC). L74VI occurred in 13/153 (8.5%) patients receiving TDF and 30/54 (55.6%) receiving ABC compared with 1.8% receiving d4T or AZT (p<0.001 for both TDF and ABC). Y115F occurred in 16/153 (10.5%) patients receiving TDF and 16/54 (29.6%) receiving ABC compared with 4/720 (0.6%) patients receiving d4T or AZT . K70QEG occurred in 12/153 (7.8%) patients receiving TDF compared with 3/720(0.4%) receiving d4T or AZT (p<0.001).TAMs occurred in a higher proportion of patients receiving an AZT-containing regimen than in patients receiving a TDF- or ABC-containing regimen . However, there was no difference in the proportion of patients with TAMs between those receiving a d4T-containing regimen compared with those receiving a TDF- or ABC-containing regimen (16% vs. 18%). M184V/I  occurred in a somewhat higher proportion of patients receiving a d4T- or AZT-based first-line regimen than an ABC- or TDF-based regimen.K65R occurred in a higher proportion of patients receiving TDF plus 3TC plus NVP than TDF plus 3TC plus EFV  but there were otherwise no significant differences in the proportions of NRTI-resistance mutations between the 91 patients receiving an NVP-containing regimen compared with the 836 receiving an EFV-containing regimen.Additional NRTI resistance mutations not shown in An analysis of the complete set of RT sequences, identified two novel, possibly subtype C-associated, NRTI mutations. T165L, a nonpolymorphic mutation previously reported to be associated with NRTI therapy occurred in 1.6% (22) of patients, a proportion similar to the 1.3% found in the ∼3,600 RTI-experienced subtype C-infected patients in HIVDB but significantly higher than the 0.4% found in the ∼25,000 RTI-experienced non-subtype C-infected patients in HIVDB. S68N occurred in 1.4% (20) of patients, a proportion higher than the 0.1% and 0.3% previously found in the subtype C and non-subtype C RTI-experienced patients in HIVDB. Of note, 18 of the 20 patients with this mutation also had K65R.Additional NNRTI-resistance mutations not shown in Of the 490 patients who received an LPV/r-containing regimen, 55 (11.2%) had plasma virus samples with one or more LPV-resistance mutations. These 55 plasma virus samples comprised 36 distinct patterns of LPV-resistance mutations . OverallIn the nine years since the start of the South African National ARV Treatment Program, therapy has evolved in accordance with WHO ARV treatment recommendations. TDF and ABC have increasingly been used in place of d4T and AZT in patients receiving first-line therapy and the number of patients requiring second-line therapy with LPV/r has gradually increased The data presented in this study substantially increases the number of publicly available sequences, as of April 2013, from ARV-treated subtype C infected patients. The subtype C RT sequences from 1,398 NRTI ± NNRTI-treated patients represents nearly 40% of the ∼3,600 of such patients in HIVDB. The subtype C PR sequences from 486 LPV/r-treated patients more than double the number of all subtype C-infected patients in HIVDB.Among patients with virological failure on a first-line dual NRTI plus NNRTI regimen, a higher proportion of those who received TDF and/or ABC had the non-TAMs K65R, K70EQG, L74VI, and Y115F compared with those receiving d4T or AZT. M184V, the most common NRTI-resistance mutation, occurred in a significantly but only modestly higher proportion of patients receiving an AZT- or d4T-containing regimen compared with those receiving a TDF- or ABC-containing regimen.With the exception of infrequent mutations at codons 67 and 219, TAMs rarely occurred in patients receiving ABC plus 3TC- or TDF plus 3TC-containing first-line regimens. The fact that 21% of TDF recipients and 10% of ABC recipients had TAMs is therefore consistent with the substitution of these NRTIs for managing d4T toxicity. Such single drug switches in patients without documented virological suppression is a likely explanation for the higher than expected frequency of TAMs in TDF and ABC recipients.The high proportion of non-TAMs in patients receiving first-line TDF- and ABC-containing regimens is a striking example of HIV-1′s ability to evolve under different selection pressures. The high proportion of non-TAMs is also of concern in that the number of ARV-resistance mutations developing during virological failure is often related to the duration of failure. Indeed, the risk of K65R was significantly higher in the 20 patients receiving TDF plus 3TC plus NVP compared to the 133 patients receiving TDF plus 3TC plus EFV, a finding consistent with previous reports questioning the efficacy of TDF plus 3TC plus NVP As our study was a laboratory-based study, we were not able to evaluate the response to therapy with TDF- and ABC-containing regimens. Indeed, patients in this study who were treated with an initial TDF- or ABC-containing regimen or with TDF or ABC as a substitute for d4T may have had more advanced HIV-1 disease. However, a recent retrospective South African study of 585 patients receiving first-line therapy with TDF and 3TC plus an NNRTI was particularly informative in vitroThe distribution of NNRTI resistance mutations was consistent with previous studies: V106M was significantly more common among patients receiving EFV and Y181C was significantly more common among patients receiving NVP The 11% prevalence of LPV/r resistance among patients with virological failure on an LPV/r containing regimen is consistent with studies from the U.K. In conclusion, changes in HIV treatment practices are greatly influencing the genotypic patterns of ARV resistance and cross-resistance in patients experiencing first-line ARV treatment failure. Indeed a high proportion of patients receiving TDF or ABC had non-TAMs that were uncommonly observed in patients receiving AZT or d4T. Although TDF and ABC are more potent and less toxic HIV-1 inhibitors than d4T and AZT, the impact of their widespread introduction in South Africa requires ongoing monitoring to ensure that the efficacy of first-line therapy is not compromised, and to identify optimal second-line regimens.Currently over 1.7 million patients are on ARV therapy in South Africa and with the anticipated increased complexity of regimens as therapy history increases, an increased need for resistance testing is expected. Importantly, in order to inform national and international policy makers, genotypic data and its associated treatment regimen should be made available in public databases


Tuberculosis (TB) remains the largest cause of death among people living with HIV/AIDS, especially among those with profound immunosuppression. Case-fatality among co-infected patients occurs mainly in the first months after the TB treatment initiation. Therefore, robust data regarding optimal timing of HAART initiation within this early period is critically needed.3. Patients received standard 6-month TB treatment plus stavudine, lamivudine and efavirenz in 5 hospitals in Cambodia, 2 in Phnom Penh and 3 in province. Patients were followed for 50 weeks after the last patient’s enrollment. A log-rank test was used to compare Kaplan-Meier survival curves.The CAMELIA  clinical trial is an open-labelled randomized clinical trial designed to compare the impact upon mortality of early (2 weeks) vs. late (8 weeks) HAART initiation after TB treatment onset in treatment-naïve adults with newly diagnosed acid-fast bacilli (AFB) positive TB and CD4+ cell count ≤ 200 cells/mm2, CD4+ cell count of 25 cells/mm3 and viral load of 5.64 log copies/ml. All AFB-positive samples including sputum in 538 (81.4%) patients, were cultured. As of May 13, 2010, 149 patients were known dead . Enhanced survival was observed in the early arm . At week 50, median CD4+ gain was 114 cells/mm3 and was not statistically different across arms (p=0.22); 96.5% of patients had an undetectable viral load and again no difference across arms was found (0.82). Figure 661 patients  were enrolled with a median age of 35 yrs, body mass index of 16.7 kg/mInitiation of HAART 2 weeks after onset of TB treatment significantly improves survival in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis.


Background. Little is known about temporal trends in frequencies of clinically relevant ARV resistance mutations in HIV strains from U.S. patients undergoing genotypic testing (GT) in routine HIV care. Methods. We analyzed cumulative frequency of HIV resistance among patients in the HIV Outpatient Study (HOPS) who, during 1999–2008 and while prescribed antiretrovirals, underwent GT with plasma HIV RNA >1,000 copies/mL. Exposure ≥4 months to each of three major antiretroviral classes  was defined as triple-class exposure (TCE). Results. 906 patients contributed 1,570 GT results. The annual frequency of any major resistance mutations decreased during 1999–2008 . Resistance to PIs decreased among PI-exposed patients  as exposure to ritonavir-boosted PIs increased . Non-significant declines were observed in resistance to NRTIs among NRTI-exposed (82% to 67%), and triple-class-resistance among TCE patients (66% to 41%), but not to NNRTIs among NNRTI-exposed. Conclusions. HIV resistance was common but declined in HIV isolates from subgroups of ARV-experienced HOPS patients during 1999–2008. Resistance to PIs among PI-exposed patients decreased, possibly due to increased representation of patients whose only PI exposures were to boosted PIs. Highly active combination antiretroviral therapy (cART) has significantly improved survival and reduced the rates of AIDS-related complications among HIV-infected persons –3. EmergRecent European and Canadian studies have suggested that both the prevalence , 18 and The HIV Outpatient Study (HOPS) is an ongoing, longitudinal cohort study of HIV-infected patients in care followed at HIV specialty clinics in the US since 1993. The HOPS methodology has been described previously . In brieFor this analysis, we examined data from active participants seen at 10 HOPS clinics between January 1, 1999, and December 31, 2008, using the HOPS dataset as of September 30, 2009. Participants were considered active if they had at least two HOPS-related encounters documented , and at least one of these encounters occurred during the calendar years of interest. The study population was restricted to patients who underwent GT while receiving ARV therapy with a documented plasma HIV RNA viral load >1,000 copies/mL; we chose the measurement most proximal to the date of GT within the six months prior and two weeks after the GT during 1999–2008. Only GT results documented on or after the first HOPS visit were considered; GT results indicating insufficient virus or inadequate specimen were excluded from the analyses. “Mono-dual NRTI exposure” was defined as any prior treatment with a regimen containing only one or two NRTIs as of the last eligible genotypic test in the year of interest. “Triple-class exposure” (TCE) was defined as four continuous months of exposure to ARVs from each of the three main classes  as of the last eligible genotypic test in the year of interest; resistance to other novel drug classes was not evaluated. “Only cART exposure” was defined as having never been prescribed non-cART  regimens as of the last eligible genotypic test in the year of interest. “Triple-class resistance” (TCR) was defined as the presence or presumed accumulation  of mutations to ARVs from each of the three main classes.Using the International AIDS Society (IAS) December 2008 listing of clinically relevant mutations, we assessed the frequency of major HIV resistance mutations in viruses isolated from patients who were followed in HOPS during 1999–2008 and underwent at least one eligible genotype test during that period. For patients who had multiple genotypic tests per year, we focused on the last test. Annual frequencies of ARV resistance were calculated as the number of patients with genotype(s) that during a calendar year demonstrated resistance, or had previously demonstrated resistance (numerator), divided by the number of patients with an eligible genotype performed in that year (denominator) and expressed as a percentage. Thus, resistance was determined by the presence of either a current or previously detected mutation(s) among patients tested that year, even if a previously detected mutation(s) was no longer apparent on the most recent resistance assay. We examined resistance to each of the three main drug classes  among all ARV-treated patients and among patients known to have been specifically exposed to agents in these drug classes. We also examined the frequency of TCR among TCE patients. Because M184V is a frequently observed mutation that develops rapidly after exposure to lamivudine and emtricitabine, but which does not confer resistance to all NRTIs, we conducted alternate analyses excluding this mutation. Finally, we assessed the likely impact of excluding genotypic tests performed at HIV RNA viral load ≤1,000 copies/mL on our findings, by examining frequency of insufficient specimens and resistance patterns in this subset.P values over the 10-year period of the study. All analyses were performed using SAS version 9.1 . Statistical associations with P values <0.05 were considered significant.Resistance was assessed as of the last eligible genotypic test in the year of interest. Trends in patient characteristics and in mutation frequency were evaluated using general linear models (PROC GLM), reporting The 6,158 HOPS patients under observation during 1999–2008 had a total of 3,305 GT results during this period. We identified 1,867 (56%) genotypic tests performed while the patients were prescribed ARVs, of which 1,570 (84%) were performed when the most proximal HIV RNA was >1,000 copies/mL. These 1,570 GT results were obtained from a total of 906 patients, of whom 541 patients contributed one eligible GT result, 206 contributed two results, and 159 contributed ≥3 results. Taking the last GT result per patient per year resulted in 1,436 GT assessments for 906 unique patients being available for resistance trend analyses during 1999–2008.P < 0.0001, P < 0.0001). Furthermore, the percentage of genotypic tests performed among ARV-treated patients whose HIV RNA was ≤1,000 copies/mL  increased over time (4.5% in 1999 (6/133) versus 18.2% (16/88) in 2008, P = 0.008). See Notably, while the annual number of active HOPS participants receiving ARVs in the HOPS oscillated around 2,700 during 1999–2008, the annual number and relative proportion of participants receiving ARVs who had at least one documented episode of viremia  decreased markedly from nearly 1,400 to fewer than 500 participants  to be older, female, of non-Hispanic black race/ethnicity, to have reported heterosexual risk for HIV infection, and to have been publicly insured , 11% were injection drug users at the time of HIV diagnosis, and 29% were heterosexuals . As of t insured . The med insured .P = 0.012), while the percentage with any prior PI exposure remained stable  and the percentage with ritonavir-boosted PI exposure increased markedly  (P < 0.001), while the fraction of cART-only exposed participants increased , and the fraction of participants with TCE remained unchanged   . The ann = 0.11) .P = 0.054) and for persons with mono-dual NRTI exposure  but not among persons who were exposed only to cART  or who had TCE   , part A. = 0.43) , part A.Among all patients receiving genotypic tests, regardless of their ARV regimen exposures, the frequency of any major resistance mutations (88% to 79%) , part B.P = 0.094) among NRTI-exposed patients and to NNRTIs  among NNRTI-exposed did not decrease significantly, but the frequency of resistance to PIs  among PI-exposed did (P = 0.094)  .In the sensitivity analyses that excluded the M184V mutation in reverse transcriptase, the frequency of NRTI resistance was 10–15% lower in each given calendar year, but the frequency of TCR decreased by <5% in each year (data not shown). Furthermore, when we restricted analyses to the first or the last genotypic test per patient during 1999–2008, to avoid correlated outcomes in the analyses, the declines in resistance observed in the primary analyses persisted.The decrease in prevalence of PI resistance, both within the entire cohort and among persons exposed to PIs, correlated with a shift in exposures to specific PIs. The most common current or prior PI exposures in 1999 were to nelfinavir (70%), indinavir (69%), saquinavir (66%), and full-dose ritonavir (51%), whereas by 2008, the most common PI exposures were to low-dose ritonavir for PI boosting (75%), lopinavir (65%), atazanavir (53%), and indinavir (40%). Furthermore, we did not see a trend whereby exposure to PIs (as a class) was increasingly distanced from the date of genotype . In each calendar year, among patients who had any PI exposure to date, over 75% underwent GT while being prescribed at least one PI agent. In supplemental analyses, we compared the frequency (non-cumulative) of resistance mutations detected in each patient's most recent viral isolate from 2004–2008, according to HIV RNA level at GT, contrasting results for patients whom we included  and excluded  in our primary analyses. Of 624 unique patients who had their last GT while on ARVs in that period, 42 (7%), and 143 (23%) patients, respectively, had GT performed with the closest HIV RNA in the range of 500–1,000 copies/mL and <500 copies/mL. The percentages of patients missing GT results because of “insufficient specimen” were 2%, 12%, and 46% in samples with HIV RNA >1,000 copies/mL, 500–1,000 copies/mL, and <500 copies/mL, respectively. In the remaining evaluable isolates, the frequency of any major IAS resistance mutation was 76%, 76%, and 47% for the three HIV RNA strata, respectively.As treatment options for HIV-infected patients have improved over time in terms of greater effectiveness, tolerability, and sheer number of available antiretrovirals, we found that a decreasing proportion of ARV-treated patients in our diverse US-based cohort had viremia and thus were candidates for GT to optimize cART . Among AThe magnitude and temporal trends in the frequency of resistance mutations among HIV strains isolated from patients who undergo GT can be influenced by a myriad of factors, including but not necessarily limited to (i) changes in the sociodemographic and clinical characteristics of the patient population over time, particularly in a dynamic cohort such as the HOPS in which patients can enter or leave care; (ii) changes in the nature and extent of ARV exposure over time ; (iii) more widespread utilization of GT and changes in the characteristics of patients considered appropriate candidates for such testing; (iv) archiving of mutations in the absence of selective antiretroviral drug pressures; (v) cohort-level changes in the degree of patient adherence to prescribed ARVs and the related likelihood of experiencing viremia while prescribed cART.It is important to note that our findings regarding the extent of and trends in the frequency of ARV resistance mutations apply only to the decreasing annual proportion of HOPS patients eligible for resistance testing , that isAlthough we did not detect statistically significant declines in the frequency of any ARV resistance among HIV strains from all HOPS patients who underwent GT in clinical practice and among the subset who were solely cART-experienced, recent population-based studies provide supporting evidence for such declines. These studies suggest that the incidence of ARV resistance is decreasing , 20 due We also found that HOPS patients who underwent GT were increasingly less likely to have virus with PI resistance, whereas potential declines in NNRTI resistance were more modest and nonsignificant over time. These trends might reflect shorter persistence of PI mutations than NNRTI mutations in the absence of drug pressure or greater use of ritonavir-boosted PIs, which are more potent and confer greater barriers to the emergence of resistance. Among ARV-naïve patients initiating cART who were followed in British Columbia, Canada, the development of ARV drug resistance was associated with the use of non-boosted PI-based or NNRTI-based regimens , suboptiWe excluded from our primary analyses genotypic tests performed on plasma HIV RNA samples with ≤1,000 copies/mL because such assays may provide unreliable results  due to insufficient HIV RNA copy and such patients may have low level self-limited viremia  rather than true virologic failure. Indeed, when comparing results from genotypic tests performed when HIV RNA >1,000 copies/mL versus ≤1,000 copies/mL in the latest years of the study, we found that the frequency of “insufficient specimens” was higher, while the frequency of detected resistance was lower in the latter group, especially when HIV RNA <500 copies/mL. Aside from concern for bias due to nonevaluable samples, including the relatively few results from genotypic tests performed with HIV RNA between 500 and 1,000 copies/mL would have likely accentuated the observed decreases in the frequencies of resistance at GT through 2008. Our analytic approach ensured more comparable data over time, and the declines in resistance we observed are likely conservative.Our findings suggestive of declines over time in rates of ARV resistance are notable for at least two reasons. First, because of the method we employed to analyze cumulative frequency of ARV resistance to date, by “carrying forward” previously identified mutations that may have become archived, the frequency of resistance in later years should tend to be higher  than would be suggested if results were based on a single genotypic test that year. Further, one might expect to find higher overall frequency of mutations over time, as newer ARVs are added to the three drug classes, with new, often ARV-specific, resistance mutations being identified and detected using contemporary genotypic tests.We believe that three factors most likely explain the lower frequency of resistance among HOPS patients who underwent GT over time: (i) the increasing use of more tolerable and potent cART regimens associated with higher barriers to resistance or more complex mutational pathways necessary for resistance to develop; (ii) the decreasing proportion of HOPS patients under observation having mono-dual NRTI exposure; (iii) the increasing and more widespread use of GT in the HOPS with possible testing of patients at lower risk of virologic failure due to resistance. The decreasing frequency of resistance to PIs in our population was associated with increased use of more potent PIs . This trend could have also occurred if exposures to PIs were increasingly distant, which would have allowed greater opportunity for PI resistance mutations to become archived before patients underwent GT. However, we found no evidence that the time between PI exposure among exposed patients and time of genotypic test differed over the study observation period.In a cohort study of 1,587 HIV-infected patients at the University of North Carolina (2000–2006), of whom 607 had at least one genotype, there were 27.2% of patients with TCR among 437 patients who had GT and any exposure to each of the three drug classes. This was lower than the 40.6% estimated for patients with TCE in our study, possibly because we required a minimum of three months of exposure on each of the three drug classes to define TCE . Our finThe findings from our ecological analyses should be interpreted in light of several additional caveats and limitations. First, most patients receiving antiretrovirals in the HOPS were virologically suppressed and, over time, fewer were eligible for GT during the study period, resulting in a progressively smaller and more select sample of patients with GT results, raising the concern for potential bias and limiting statistical power. Second, we relied on data collected in the course of regular HIV care since our purpose was to reflect what a treating clinician would see. Not all eligible patients had GT performed, and trends in and magnitude of resistance frequencies detected may have been different if all ARV-experienced, viremic patients had undergone scheduled GT at regular intervals . Third, In conclusion, the frequency of ARV resistance mutations detected for HIV among patients in the HOPS who were tested in the course of routine clinical practice was high and tended to decrease during 1999–2008. The decreasing frequency of genotypic resistance corresponded with at least two trends: an increasing use of more tolerable and potent cART, including boosted PI regimens, and a decreasing proportion of HOPS patients with histories of exposure to mono- and dual-NRTI ARV regimens. Our findings support the continuing need for routine HIV resistance testing and monitoring of evolving ARV resistance patterns among ARV-treated patients  who expe


Palmoplantar erythrodysesthesia is an uncommon localised cutaneous reaction to certain chemotherapeutic agents and characterized by painful palmoplantar erythema and dysesthesia. To the best of our knowledge, we report the first case of plantar erythrodysesthesia in a 40-year-old male patient receiving an antiretroviral combination therapy for HIV. Palmoplantar erythrodysesthesia (PPE), known as hand-foot syndrome is an uncommon, distinct, localised cutaneous reaction in patients treated with high dose chemotherapy , 2. It iA 40-year-old Caucasian male, who had been diagnosed for HIV infection in 2004, presented with plantar erythema, dysesthesia, pruritus, and desquamation of the skin. The symptoms were recurrent with varying severity. Upon dermatological examination his soles displayed erythematous macules and exfoliation, affecting the whole plantar region . His perWe report the case of repetitive occurrence of plantar erythema, dysesthesia, pruritus, and desquamation in a 40-year-old male caucasian patient with HIV infection and antiretroviral combination therapy.The pathophysiology of PPE is still unknown and several mechanisms have been proposed , 2. It hDose reduction or interruption of medication is the only causal evaluated treatment options in PPE described so far . MoreoveEspecially in patients suffering from HIV, the identification of a causative single antiretroviral drug is complicated, because most patients are treated with combined therapies and discontinuation is not possible. Cutaneous adverse effects are not uncommon . HoweverAs cutaneous reactions due to ritonavir, lopinavir, and tenofovir are rare  and the Patients receiving antiretroviral drugs frequently experience cutaneous side effects. To avoid treatment interruptions of life-saving medication, early recognition, understanding of pathogenesis, and adequate therapy for this predominantly dose limited syndrome are crucial. We recommend greater vigilance for palmoplantar erythrodysesthesia in patients, treated with lopinavir, ritonavir, emtricitabine, and tenofovir.


For various reasons it can be necessary to administer antiretrovirals permanently or temporarily in a dissolved form: swallowing difficulties, stomach tube or patients in an ICU. However, not all drugs are available as oral solution. Crushing and dissolving may be an option, but data on plasma levels and efficacy are limited or not existing.We report efficacy and plasma level data for two patients, one with dysphagia and Candida esophagitis and one with a stomach tube, who received darunavir (DRV) crushed and dissolved.3 and candida esophagitis. HAART was initiated with DRV/RTV 600/100 mg in combination with etravirine (ETR) and raltegravir (RAL). DRV and RAL tablets were crushed, ETR was suspended and ritonavir (RTV) was given as oral solution. The medication was well accepted with exception of RTV oral solution. Trough levels (10 h post dose) for DRV were 6.950 ng/mL; measured one month post treatment initiation. At that time, VL had declined to 102 copies/mL; CD4 count had increased to 111 cells/mm3. The patient was then switched to tablets, viral load has been <40 copies/mL since then.Patient 1 is 57 year old HIV+ male (CDC C3), first diagnosed in 1990, who has been on various antiretroviral regimens since 1992. He presented with a VL of 72.551 copies/mL, 56 CD4 cells/mm3. Plasma levels for DRV were within the therapeutic range: 4.430 ng/mL (5 hours post dose) in January and 5.210 ng/mL (3 hours post dose) in June.Patient 2 is a 48 year old HIV+ paraplegic woman (CDC C3), first diagnosed in 2004 with a permanent stomach tube. HAART with DRV/RTV 600/100 mg bid, RAL and tenofovir/emtricitabine via tube was initiated in 2008. Since then, viral load has been permanently < 40 copies/mL; CD4 count is stable between 440 and 540 cells/mmCrushing DRV tablets and combining them with RTV oral solution reached adequate DRV plasma levels. In these two patients, HAART administered via artificial feeding was an effective option for short and long-term treatment.


To compare the effectiveness of first-line combination antiretroviral therapy (cART) between premenopausal and postmenopausal women.ART-naïve women initiating cART between January 2000/June 2010 at the Instituto de Pesquisa Clínica Evandro Chagas Cohort were studied. Women were defined as postmenopausal after 12 consecutive months of amenorrhea. CD4 cell counts and HIV-1 RNA viral load (VL) measurements were compared between pre- and postmenopausal at 6, 12 and 24 months after cART initiation. Women who modified/discontinued a drug class or died due to an AIDS defining illness were classified as ART-failures. Variables were compared using Wilcoxon test, χ2 or Fisher’s exact test. The odds of cART effectiveness (VL<400 copies/mL and/or no need to change cART) were compared using logistic regression. Linear model was used to access relationship between CD4 change and menopause.3 (p = 0.14) in pre- and postmenopausal women, respectively. No difference in the median pre cART VL was found (both 4.8 copies/mL). Median CD4 changes were similar at 6 and 12 months. At 24 months after cART initiation, CD4 changes among postmenopausal women were significantly lower among premenopausal women (p = 0.01). When the analysis was restricted to women with VL<400 copies/mL, no statistical difference was observed. Overall, 63.7% achieved cART effectiveness at 24 months without differences between groups at 6, 12 and 24 months.Among 383 women, 328 (85%) were premenopausal and 55 (15%) postmenopausal. Median pre cART CD4 counts were 231 and 208 cells/mmMenopause status at the time of first-line cART initiation does not impact CD4 cell changes at 24 months among women with a virologic response. No relationship between menopause status and virologic response was observed. Women account for 50% of people living with HIV, the majority of them living in low and middle-income countries The expansion of combination antiretroviral therapy (cART) coverage was crucial to reduce HIV-related morbidity and mortality rates turning HIV infection into a chronic condition. Antiretroviral therapy (ART) global coverage has significantly grown in the latest years, with 11.7 million life-years added to the world between 1996 and 2008 The number of older women who will become HIV-infected or who will live with HIV is expected to increase as overall life expectancy increases, and many of them will undergo menopause during the course of the HIV disease Recent studies have shown that aging has very specific effects on T cell function Several studies have evaluated the influence of gender and age on cART outcomes Data on the cART outcomes in HIV-infected postmenopausal women remain scarce, especially in low- and middle-income settings, including Brazil, where universal access to cART free of cost has been provided by the Ministry of Heath since 1997. The purpose of this study was to compare the effectiveness of first-line cART among HIV-infected pre- and postmenopausal women in a cohort of HIV-infected women in Rio de Janeiro, Brazil.The study protocol was reviewed and approved by the ethics committee of Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (CAE 0032.0.009.000-10). Written informed consent was obtained from all women.This study was conducted at the Instituto de Pesquisa Clínica Evandro Chagas (IPEC) AIDS Service at Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil, where care has been provided to HIV/AIDS patients since 1986. An observational, longitudinal, clinical database is maintained on patients receiving primary and specialized HIV care at the clinic. Details of the HIV/AIDS cohort can be found elsewhere For this study, data from 386 antiretroviral-naïve women who initiated cART between January 1, 2000 and June 30, 2010 were considered. Women without gynecological data defining menopause status were excluded (N = 3). Thus, we analyzed data from 383 cART-naïve patients who initiated cART within the study period. Follow up information includes data up to September 30, 2011.Menopausal status was prospectively captured during bi-anual interviews. Women were defined as postmenopausal after twelve consecutive months of amenorrhea, for which there was no other obvious pathological or physiological cause Race was based on provider report and categorized as white and nonwhite.cART was defined as two nucleosides transcriptase reverse inhibitors (NTRI) in combination with one non nucleoside transcriptase reverse inhibitor (NNRTI) or one protease inhibitor (PI); antiretroviral regimens were classified as NNRTI or PI-based. The calendar year of cART initiation was stratified into two groups: 2000–04 and 2005–09.Drug class modifications and discontinuation were defined as any NNRTI or PI drug modification or interruption (including deaths due to AIDS defining illnesses). Neither NTRI substitutions nor regimen dosage adjustments were considered regimen modifications.3) measurement recorded closest to the time points were evaluated.The effectiveness of first-line cART at 6, 12 and 24 months was defined as an HIV-1 RNA viral load (VL) measurement of less than 400 copies/mL at these time points without drug class modification. Window periods were defined for each time point as 5–9 months, 9–15 months, and 21–27 months, respectively. Within each window, the viral load and CD4 cell counts  and baseline HIV-1 RNA as any available value obtained before or up to 7 days after cART initiation. CD4+ cell counts and HIV-1 RNA results were obtained from the medical records. CD4+ cell counts were categorized into <200, 200–500 and >500 cells/mmCD4+ T-cell counts samples were evaluated on a BD FACSCalibur cytometer . The assays used for measurement of HIV-1 viral load were nucleic acid sequence–based amplification , Roche Amplicor reverse transcriptase polymerase chain reaction (RT-PCR) assay  and branched DNA assay, Versant HIV-1 RNA 3.0 . The assays used for measurement of HIV-1 viral load varied according to the year and whether or not the woman was enrolled in a clinical trial. For the purpose of statistical analysis, the cut-off value, defined as undetectable VL, was set as a VL ≤400 copies/mL, regardless of the method used.AIDS defining illnesses (ADI) was defined as the presence of any 1993 Centers for Disease Control and Prevention (CDC)-defined ADI Participation in a clinical trial was defined when a patient started their first-line regimen in a cART-naïve clinical trial.-squared test or Fisher’s exact test. Median changes in CD4 cell counts and HIV-1 RNA VL measurements were compared between pre- and postmenopausal women at 6, 12 and 24 months after cART initiation.Quantitative variables between pre- and postmenopausal women were compared using Wilcoxon test. Categorical variables were compared using chiWe calculated the odds ratio for effective cART and the 95% confidence interval (95%CI) of first-line cART at 6, 12 and 24 months after treatment initiation, adjusting for baseline log 10 VL, baseline CD4, cART regimen and ADI, using logistic regression model.The impact of missing VL measurement on the effectiveness of first-line cART was evaluated in a sensitivity analyses. We compared the estimates and confidence intervals of three different models. 1) Model A: when individuals with missing VL measurements were excluded; 2) Model B: when the missing VL measurements were coded as 1  and; 3) Model C: when the missing VL measurements were coded 0 .Linear regression was used to access the relationship between CD4 change and menopause at 6, 12 and 24 months. In the other analyses, immunological reconstitution was defined as a >25% increase in CD4 cell count from baseline and logistic regression was used to access the menopause effect at 6, 12 and 24 months. All models were adjusted for baseline log 10 VL, baseline CD4, cART regimen and ADI.www.r-project.org).For all statistical analyses we used the statistical software R, version 2.14.2 (P<.001). A hysterectomy history was more frequent among postmenopausal women .Among 383 women, 328 (85%) were premenopausal and 55 (15%) postmenopausal. Demographic and clinical characteristics are shown in p = 0.14) in pre- and postmenopausal women, respectively. No difference in median pre cART VL was observed (both 4.8 copies/mL). Almost two- thirds of the study population initiated cART between 2005 and 2009. NNRTI-based cART was the most frequently prescribed . Approximately 40% of all women initiated cART within a clinical trial.Median pre-cART CD4 counts were 231 (IQR:132–334) and 208 (IQR:85–287) cells/mm3  and 12 months . At 24 months after cART initiation, CD4 median changes among postmenopausal women were significantly lower than among premenopausal women   .p = 0.99), 12 , and 24 months   . No diff = 0.60) .There were no differences in the odds ratio of achieving an HIV-1 RNA level <400 copies/mL for premenopausal compared with postmenopausal women after adjusting for baseline log10 HIV-1 RNA levels, baseline CD4, cART regimen and ADI at 6 months , 12 months , and 24 months  . Sensiti3; SE: 39.9 cells/mm3) than premenopausal women (p = 0.01). This difference was not observed when analysis was restricted to women with VL<400 copies  (p = 0.26) (At 24 months after cART initiation (and after adjusting for the same covariates), postmenopausal women had significantly lower CD4 cell changes (−97.8 cells/mm = 0.26) .When immunological reconstitution was evaluated as a >25% increase in CD4 cell count from baseline, no statistical differences were observed in unadjusted or adjusted analyses comparing pre- and postmenopausal women at 6, 12 and 24 months after cART initiation in the overall group or when the analysis was restricted to virologically suppressed women  and 4.Our results demonstrated that menopause status at the time of initiation of first-line combination antiretroviral therapy does not impact CD4 cell count changes at 24 months among women with virologic response, regardless of the ART class prescribed, year of ART initiation or having started ART in a clinical trial as compared to regular care. Nevertheless, CD4 median changes remained lower among postmenopausal women.We found no evidence of any interaction between menopause and virologic responses. To our knowledge, our analysis is the first to report virologic and immunologic outcomes following cART initiation in women from a middle-income country stratified by menopause status.Most cohort studies found that overall, older people can achieve treatment success rates similar to younger individuals Several studies have shown a decreased CD4 cell response among older patients, regardless of sex, and some of them have observed increased HIV disease progression and a negative impact on survival Abrogoua et al, in a study conducted in a resource-limited setting, found that age and baseline clinical status had no significant influence on immunological outcomes at 24 months, although an optimal CD4 cell response was significantly influenced by adherence Paterson et al, in an analysis comparing the effect of sex by age strata, did not find differences at 6 months from the initiation of a first HAART regimen among previously ART naïve patients in either immunological reconstitution or virological response. The potency of a first HAART regimen in controlling HIV-1 replication and subsequent immunological reconstitution have probably been able to mask any more subtle effect of biological sex differences on treatment responses Our results are reassuring that women can be treated similarly irrespective of age. Our analysis, however, did not include evaluations of antiretroviral-related toxicities or other adverse events which have been reported to be increased among older individuals and women including in our cohort Strengths of this study include a large urban cohort of women receiving HIV clinical care coupled with specialized gynecological care with prospective standardized bi-annual data collection on reproductive health, which reduces the risk of recall bias in regards to age at menopause.Limitations of this study include the retrospective nature of the HIV clinical and laboratory data collection, and a certain level of missing data on CD4 and viral load, although sensitivity analysis did not show potential selection bias. Moreover, the lack of adherence data precluded a systematic adherence evaluation.In summary, in our study population, menopause status at cART initiation did not impact long-term immunological outcomes in women with favorable virologic responses. We found no evidence of an interaction between menopause status and virologic responses. These results are reassuring, given the increasing number of older HIV-infected women initiating cART and the impact of immune reconstitution on long-term survival.


An increasing number of people on antiretroviral therapy (ART) in sub-Saharan Africa has led to declines in HIV related morbidity and mortality. However, virologic failure (VF) and acquired drug resistance (ADR) may negatively affect these gains. This study describes the prevalence and correlates of HIV-1 VF and ADR among first-line ART experienced adults at a rural HIV clinic in Coastal Kenya.HIV-infected adults on first-line ART for ≥6 months were cross-sectionally recruited between November 2008 and March 2011. The primary outcome was VF, defined as a one-off plasma viral load of ≥400 copies/ml. The secondary outcome was ADR, defined as the presence of resistance associated mutations. Logistic regression and Fishers exact test were used to describe correlates of VF and ADR respectively.Of the 232 eligible participants on ART over a median duration of 13.9 months, 57 (24.6% [95% CI: 19.2 – 30.6]) had VF. Fifty-five viraemic samples were successfully amplified and sequenced. Of these, 29 (52.7% [95% CI: 38.8 – 66.3]) had at least one ADR, with 25 samples having dual-class resistance mutations. The most prevalent ADR mutations were the M184V (n = 24), K103N/S (n = 14) and Y181C/Y/I/V (n = 8). Twenty-six of the 55 successfully amplified viraemic samples (47.3%) did not have any detectable resistance mutation. Younger age  and unsatisfactory adherence  were strong correlates of VF. Younger age, unsatisfactory adherence and high viral load were also strong correlates of ADR.High levels of VF and ADR were observed in younger patients and those with unsatisfactory adherence. Youth-friendly ART initiatives and strengthened adherence support should be prioritized in this Coastal Kenyan setting. To prevent unnecessary/premature switches, targeted HIV drug resistance testing for patients with confirmed VF should be considered. By the end of 2011, approximately 34 million people were living with HIV globally, with almost all (97%) coming from low and middle income countries (LMIC) . HoweverRegular virological monitoring has been shown to be useful both in resource rich and resource limited settings ,8. HowevA systematic review of virological efficacy and drug resistance outcomes of patients on ART programmes in sSA has reported 76% virological suppression after 12 months on ART and 67% after 24 months . SimilarEmerging drug resistance and subsequent treatment failure poses a major concern for HIV programs in resource-limited settings where treatment options are limited. This study aimed to describe the prevalence and correlates of HIV-1 virologic failure and acquired drug resistance among first-line ART-experienced adults from a rural HIV clinic in coastal Kenya.The study was carried out at the HIV clinic in Kilifi District Hospital; a rural public health facility located in Coastal Kenya. HIV services in the clinic are provided according to the Kenyan national guidelines . In brieAt the time of the study, the national recommended first-line therapy comprised two NRTIs (stavudine/zidovudine and lamivudine) and one NNRTI (nevirapine/efavirenz). A gradual phase-out of stavudine as a first-line agent was recommended in mid-2010. Adherence counseling was done by nurse counselors. Individuals failing first-line therapy were switched to an alternative combination of two NRTIs and a boosted protease inhibitor (bPI) as the recommended second line of choice.At the time of the study, routine HIV-1 virologic monitoring and drug resistance testing were not recommended in the Kenyan national guidelines. Targeted viral load monitoring was introduced in 2011. A switch to the recommended second line regimen was recommended for individuals with virologic failure .For this study, remnant blood from routine CD4 count samples was centrifuged to obtain plasma, which was archived at −80 degrees centigrade and used for viral load quantification and HIVDR testing.An analytical cross-sectional study design was used. We included HIV-infected adults (≥15 years old) who had been on first-line ART for more than six months. Participants with a previous history of ART exposure for prevention of mother to child transmission (PMTCT) or for post-exposure prophylaxis (PEP), and those on second line regimens were excluded from the study.Eligible participants were recruited in two phases. In the first cross-section, all consenting eligible participants were recruited between November 2008 and January 2009. At the same time, a prospective cohort was established in order to describe long-term outcomes of new clients enrolling for HIV care. All available plasma samples from participants recruited in the prospective cohort and meeting our eligibility criteria as at March 2011 were cross-sectionally retrieved.These have been previously described elsewhere . In brieClinical data including anthropometry, opportunistic infections, WHO staging, ART regimen, drug substitutions, drug pick up dates and appointments were routinely collected by trained clinicians on standardized forms at every clinic encounter. Hematology and CD4 T-cell count data were also collected. A trained data entry clerk entered these data into an electronic data system.Medicine Possession Ratio (MPR), defined as the amount of time a participant is in possession of antiretrovirals divided by the time between ARV drug pick-ups, is increasingly being used as a proxy for assessing adherence in retrospective analyses. We therefore retrospectively retrieved pharmacy drug refill data from 12 months (or from the date of ART initiation if follow up period <12 months) prior to the date of sampling for every individual participant. MPRs were calculated as proportions of the total number of days between drug pick-ups less the equivalent number of days in possession of ART divided by the time between drug pick-ups for all visits. A mean MPR for each individual was computed, subtracted from 100% and stratified to satisfactory (≥95%) and unsatisfactory (<95%) adherence according to previously published conventions ,20.The primary outcome was HIV-1 virologic failure (VF), defined as a one-off HIV-1 plasma RNA viral load of ≥400 copies/ml. Viral load quantification was done using an in-house assay. In brief, a multiplex real time quantitative probe-based assay with an internal control and a series of quantified HIV-1 standards was used to determine virus concentration. The assay is designed to quantify HIV-1 plasma RNA for thresholds of 100 – 10,000,000 copies/ml.pol sub-genomic region containing the protease and part of the reverse transcriptase genes. Sequences were manually edited and assembled against a reference sequence using Sequencher software . Sequences were submitted to the Stanford HIV drug resistance database to identify and interpret HIV-1 drug resistance mutations ), married (n = 132 [57%]), with a primary education or less (n = 187 [81%]) and living within 10 kilometers of the clinic (n = 148 [64%])  demonstrated VF. In univariable analysis, MPR adherence, age group and marital status were significantly correlated with VF. In multivariable analysis, only MPR adherence and age group remained independently associated with VF  had at least one detectable HIV-1 resistance associated mutation, giving an overall ADR prevalence of 12.5% (95% CI: 8.5 – 17.5) among all participants included in the study. While all 29 samples had mutations conferring resistance to NNRTIs, 25 (86%) of those with resistance had dual-class (both NRTIs and NNRTIs) mutations   met this criterion of HIV-1 VF. Of these, 28 (58.3% [95% CI: 43.2 – 72.4]) had at least one detectable HIV-1 resistance mutation. Correlates of VF  and NNRTIs . These results are consistent with findings from systematic reviews of studies on virological efficacy and drug resistance from other resource limited settings ,26. The The WHO recommends use of drug-refill data as an early warning indicator (EWI) of HIV treatment failure and drug resistance . Recent The current study also indicated younger age as a strong risk factor for both HIV-1 VF and ADR. In fact, half of all participants aged 15–24 years had VF, while two in every five had acquired at least one drug resistant strain. Data from a developed setting suggests that the youth face a complex myriad of challenges including peer-related stigma, disclosure, adherence, sexual, reproductive and gender health concerns . If applnd line regimen prematurely or unnecessarily, thus exhausting and limiting treatment options. This is especially risky in this setting where the only currently recommended second line option is the bPIs, with costs prohibiting the range of other potential alternative regimens.Higher viral load was strongly associated with ADR, which is consistent with literature . Of inteThe findings of this study should be interpreted in light of several limitations. Firstly, the cross-sectional study design and the one-off sampling strategy warrant caution in the interpretation of our findings, as follow up samples were not available to confirm VF. Consequently, blips in viral load cannot be ruled out . It is aSecondly, it may be argued that the participants may not have achieved virological suppression in the first place, even after being on ART for more than 6 months. This may possibly be attributed to the effect of persisting HIV-1 primary or transmitted resistance mutations, which have been reported to be on the increase in some parts of sSA ,38. TranLastly, stigma, disclosure, sexual orientation, reproductive health and gender issues are potential concerns that may contribute to the burden of VF and ADR, especially among the young adults in this setting. Data on these factors were not captured and hence not considered in the analyses.In conclusion, levels of HIV-1 VF and ADR observed from this rural HIV clinic in coastal Kenya were comparable to those observed in other resource-limited settings. High levels of VF and ADR were observed among younger patients and those with unsatisfactory adherence. Implementation of youth-friendly ART initiatives  are therefore warranted in this setting. Strengthened adherence support should also be prioritized, more so in cases of suspected virologic treatment failure and before treatment switches. However, if virologic failure is confirmed, targeted HIVDR testing should be considered to prevent unnecessary/premature switches.The authors declare that they have no competing interest.JAB and PAC conceived the study. ASH coordinated the data/sample collection, analyzed the data and prepared the draft manuscript. SM, HN and CAO assisted with the coordination of the data and sample collection. JAB, PAC, ES and TFRW provided guidance and mentorship during the implementation of the study. All authors reviewed and approved the final manuscript.Table S2. Distribution and correlates of HIV-1 acquired drug resistance  among first-line antiretroviral experienced adults at a rural HIV clinic in coastal Kenya (N=230).Logistic regression analysis describing correlates of HIV-1 virologic failure  among first line antiretroviral experienced adults at a rural HIV clinic in coastal Kenya (N=232). Click here for file


Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor available in France since 2006, is indicated for the treatment of HIV-1 infection in combination with a ritonavir boosted protease inhibitor (PI) in antiretroviral treatment-experienced adult patients. To assess its impact in routine clinical care, our objective was to compare hospitalization rates in highly pre-treated failing HIV-1 infected individuals between 2005 and 2011 depending on whether or not they received ETR+PI.From the French Hospital Database on HIV (ANRS CO4), we selected highly pre-treated individuals  with a viral load (VL)>50 copies/mL initiating a new regimen between 2005 and 2011. Hospitalization rates were calculated for each calendar month and depending on whether patients never received ETR+PI at any time or during months before initiating ETR+PI (no ETR+PI) or during months after initiating ETR+PI (ETR+PI), using an intention to continue treatment approach. Poisson regression models were used to compare incidence between the two groups, after adjustment for potential confounders .3, 17.5% had VL >100,000 copies/ml, 42.8% had had an AIDS event and 47.8% had received more than 10 different antiretroviral drugs. There were 2484 hospitalizations in 808 individuals over 13,986 patient-years. The hospitalization rates for 1000 P-Y were 169.0 for the ETR+PI group and 179.3 for the no ETR+PI group. After adjustment, the corresponding figures were 144.8 for 1000 P-Y and 192.7 for 1000 P-Y respectively, with a relative risk estimated as 0.75 (95% CI 0.67–0.84).Overall 3884 patients fulfilled inclusion criteria. Among them 838 (21.6%) received ETR+PI at least once. Among all enrolled patients, 35.8% had CD4 <200/mmAccess to ETR+PI between 2005 and 2011 was associated with a 25% reduction in the hospitalization rate among highly pre-treated failing HIV-1 infected individuals.


The CD4 count did not behave different between the groups along the time. This observation might be due to the higher treatment time in coinfected patients , provided that in the end of therapy they were failing on the ARV but the paired analyze with viral load must be done whereas there is an inverse correlation between CD4 count and viral load. There was no difference regarding the age and gender between the groups. HIV-1/HTLV-1 co-infection seems to change the CD4 count ratio between positive and negative individuals on ARV.To understand the impact of HTLV-1 in the CD4 counts in HIV coinfected patients from KwaZulu-Natal, 382 HIV-1 plasma samples with ARV failure were screened for HTLV-1. Out of 382 samples, eight were reactive in the EIA and seven were confirmed as HTLV-1 positive by PCR. The data from those patients was obtained in the RegaDB and was analyzed regarding the CD4 count using the STATA software. The prevalence of coinfection was 1.8% (7/382). The baseline CD4 count did not show statistical difference between groups before treatment. The overall CD4 count median during the ARV in coinfected patients (301cells/uL) was higher than in HIV-1 infected patients (232cells/uL


Objective: To evaluate the efficacy and the safety of simplification to darunavir (DRV)/ritonavir (r)/maraviroc (MVC) in virologically HIV-suppressed patients and to explore the effect of simplified treatment on coinfected patients.HIV/HCV coinfection is a risk factor for hepatic injury in patients receiving HAART and previous studies support a favourable effect of antiretroviral regimens including maraviroc (MVC) on the course of coinfection compared with other antiretroviral drugs. There are few observations about MVC use in simplified treatment of coinfected patients.GUSTA study is a randomized two arms trial that compares the switch to DRV/r/MVC with standard HAART with three drugs. The study enrols patients with HIV-1 RNA<50cp/mL>6 months, R5 tropism, CD4>200 cells/mm. Survival analysis was used to analyze factors associated to time-to a single viral load (VL) over 50cp/mL and FIB-4>1.45.We included 62 patients with at least the 24 week follow-up for FIB-4 analysis: males 75.8%, heterosexuals 48.4%, HCV+12.9% median age 48.3 years , time from HIV diagnosis 11.0 years , CD4 cells 659/mm , nadir CD4 203/mm , FPR 46 , baseline (BL) FIB-4 1.11 . At BL no differences were observed in the two arms, except for platelets  and CD4 at nadir . After 24 weeks a significant reduction in total bilirubin (TB)  and alkaline phosphatase(AP)  was observed in the study group. A statistically significant difference in mean change of TB  and AP  at 24 week between control and study group was observed. No grade 3/4 transaminase elevation was observed for any patient even if HIV/HCV coinfected and receiving MVC. A single HCV negative patient in the control arm had grade 3 bilirubin increase. Including all patients with at least one follow-up HCV status was not associated with an increased risk of detectable VL , nor with FIB-4>1.45 .The initial results from GUSTA study show that ART-regimen including MVC did not increase the incidence of adverse events or severe laboratory liver abnormalities in HIV-1-infected patients with or without HCV coinfection. Coinfected patients did not show an increased risk of failure on simplification treatment with MVC/DRV/r.


One dose of benzathine penicillin G (BPG) has been recommended for HIV-infected patients with early syphilis  in the sexually transmitted diseases treatment guidelines, but clinical data to support such a recommendation are limited.We prospectively observed the serological response to 1 or 3 weekly doses of BPG in HIV-infected adults who sought treatment of early syphilis at 8 hospitals around Taiwan. Rapid plasma reagin (RPR) titers were followed every 3–6 months after treatment. The serological response was defined as a 4-fold or greater decline in RPR titers at 12 months of treatment. The missing values were treated by following the last-observed-carried-forward principle. We hypothesized that 1 dose was non-inferior to 3 weekly doses of BPG with the non-inferiority margin for the difference of serological response set to 10%.Between 2007 and 2012, 573 patients completed at least 12 months of follow-up: 295 (51.5%) receiving 1 dose of BPG (1-dose group) and 278 (48.5%) 3 doses (3-dose group). Overall, 198 patients  in the 1-dose group achieved serological response at 12 months, as did 208 patients  in the 3-dose group . In the multivariate analysis, secondary syphilis , RPR titer ≥32 , and 3 doses of BPG  were independently associated with a serological response. The time to the first episode of treatment failure was 1184  and 1436  days for 1- and 3-dose group, respectively.Single-dose BPG resulted in a higher serological failure rate and shorter time to treatment failure than 3 weekly doses of BPG in the treatment of early syphilis in HIV-infected patients. Treponema pallidum, is an important sexually transmitted disease. Globally, there were an estimated 36.4 million cases of syphilis in adults between the ages of 15 and 49 years in 2008 Syphilis, caused by Appropriate treatment of early syphilis among HIV-infected patients has been controversial because clinical studies of a sufficient sample size have been lacking. In the previous version of treatment guidelines for syphilis by the US CDC in 2006 Several studies have shown that HIV-infected patients with syphilis have higher failure rates after standard treatment, while other studies have not This multicenter, prospective observational study was conducted between January 2007 and December 2012 at 8 major hospitals around Taiwan that are designated for HIV care by the Centers for Disease Control, Taiwan, where HIV care, including cART and monitoring of CD4 count and plasma HIV RNA load, is provided free-of-charge. According to the national guidelines for HIV care in Taiwan, non-treponemal serological tests for syphilis are recommended to be performed at least once yearly and on an as-needed basis as indicated by the clinical presentations and every 3 to 6 months over a period of 2 years for those who receive treatment for syphilis. The patients who received stable cART were usually followed as an outpatient every 3 months and monitoring of immunological and virological status was performed every 3 to 6 months.Treponema pallidum particle agglutination (TPPA) test (titer ≥1∶320), for which 1 or 3 weekly doses of BPG  were administered intramuscularly. Patients with a prior history of syphilis who received treatment within 12 months before enrollment were excluded. In addition, patients were excluded if they were pregnant, received antibiotics such as penicillin, ceftriaxone, doxycycline, or macrolides for syphilis or other infections within the preceding 12 months or during follow-up, were lost to follow-up immediately after treatment, had a history of penicillin allergy, or were receiving immunosuppressants, immunomodulators, or chemotherapy. The study was approved by the Research Ethics Committee of each participating hospital and the written informed consent was waived.HIV-infected patients were eligible for this observational study, if they were 20 years or older, had early syphilis , and had reactive rapid plasma reagin (RPR) titers of 1∶4 or greater and a reactive result of Primary syphilis was diagnosed when the patients presented with reactive serologies (RPR titers >1∶4 and reactive TPPA titers) and genital, anal, or oral ulceration (chancre); secondary syphilis was diagnosed when the patients presented with reactive serologies and cutaneous rashes, mucosal lesions, generalized lymphadenopathy, or other signs; and early latent syphilis was diagnosed when the patients presented with reactive serologies and documented negative RPR or 4-fold elevation of RPR titers with exposure to patients with syphilis within the preceding 12 months T. pallidum particle agglutination test . Plasma HIV RNA loads and CD4 lymphocyte counts were quantified with the use of the Cobas Amplicor HIV-1 Monitor™ Test, version 1.5,  and FACSFlow (Becton Dickinson), respectively.Serological tests for syphilis included the RPR test  and All patients with syphilis received 1 dose or 3 weekly doses of BPG. While treatment guidelines for syphilis evolved during the 5-year study period, the decision to give 1 or 3 doses of BPG depended on the assessment of the treating physicians, which could be influenced by the characteristics of each patient. Following treatment, follow-up of RPR titers every 3 to 6 months was recommended. A standardized case record form was used to collect information on demographic characteristics, a previous history of penicillin treatment for syphilis, stage of syphilis, RPR titers at baseline and during follow-up, dose of BPG administered, receipt of cART, and CD4 count and plasma HIV RNA load.The primary endpoint of the study was achievement of serological response that was defined as a 4-fold or greater decline in RPR titers at the 12th month follow-up visit when compared with the baseline titers. The secondary endpoint included a 4-fold or greater decline in RPR titers at the 6th month follow-up visit when compared with the baseline titers; and the time to treatment failure, which was defined as the failure to achieve a 4-fold or greater decline in RPR titers; or a 4-fold or greater increase in RPR titers after achieving serological response during the 12 months of observation; or anytime when retreatment of syphilis was given during the 12 months of follow-up.P value ≤0.2 or biological significance were included in the multivariate analysis. Binary logistic regression analysis was used to determine the factors associated with serological responses at the time of 12 months of follow-up. We fit the data using mixed effect model in which the covariate structure of “hospitals” was considered in the model. Thus the factor “hospital” was treated as a random effect and was put into mixed effect binary logistic regression analysis. All comparisons were 2-tailed and a P value <0.05 was considered to be significant. We hypothesized that 1-dose BPG regimen was non-inferior to the 3-dose regimen in the HIV-infected patients with early syphilis. The non-inferiority in terms of serological response rate following 1-dose BPG therapy to 3-dose therapy would be concluded if the lower boundary of the two-sided 95% confidence interval (CI) (one-sided α = 0.025) for the difference in the serological response rate between the two groups was at least −0·1 . With the estimated serological response rate of 75% for the 3-dose BPG group, it was estimated that 232 patients were needed for each group to confirm the non-inferiority of 1-dose to 3-dose regimen with a power of 80%. Time to treatment failure was assessed by Kaplan-Meier plots and Cox proportional hazards regression analysis was used to estimate the hazard ratios (HR) for treatment failure between the two groups of patients. All patients were followed until 30 June, 2013, or the date when the patients received the diagnosis of recurrent syphilis or were lost to follow-up, or death, whichever occurred first.All statistical analyses were performed using SPSS version 18.0  and Stata software, version 10 . All patients who received at least 1 dose of BPG were included for analyses, for which the last-observed-carried-forward principle was adopted to deal with missing data at the 6th and 12th month of follow-up. Each patient was followed at least for twice during the 12-month study period. Categorical variables were compared by Fisher’s exact test or Chi-square test. Non-categorical variables were compared by Mann-Whitney U test. Factors with a During the 5-year study period, 1128 HIV-infected patients with syphilis sought HIV care and treatment of syphilis at the 8 participating hospitals, and 555 (49.2%) patients were excluded due to late latent syphilis stage (n = 408), concurrent use of other antibiotics (n = 41), loss to follow-up on the second day after treatment , low RPR titers (<1∶4) (n = 22), and without confirmed HIV infection (n = 8) . A totalBaseline characteristics of the two groups of patients are shown in P = 0.044) in the last-observed-carried-forward population (P = 0.24) (P = 0.041) in the last-observed-carried-forward population, with the one-sided 95% CI of effectiveness difference between the 3-dose and 1-dose group exceeding the predefined 10% non-inferiority margin.The serological response rate at 12 months of BPG treatment was 67.1%  for the 1-dose group and 74.8%  for the 3-dose group (pulation . In the  = 0.24) . The difP = 0.084). In the multivariate logistic regression analysis, we found that secondary syphilis , RPR titers ≥32 , and 3-dose BPG  were independently associated with a serological response . There were no statistically significant differences in the overall serological response rates before and after the change of treatment guidelines in 2010 In the two groups of patients, 88.1% and 86.0% in the 1-dose group and the 3-dose group, respectively, ever achieved a 4-fold or greater decline in RPR titers after treatment (data not shown) .During the study period, the mean observation duration was 1102 days  for the 1-dose group and 1265 days  for the 3-dose group. Overall, treatment failure developed in 146 (49.5%) and 120 (43.2%) patients in the 1-dose and 3-dose group (p = 0.13), respectively, during the follow-up; none developed clinical manifestations suggestive of neurosyphilis, however. The Kaplan-Meier survival plot to depict the time to treatment failure for the two groups of patients is illustrated in P = 0.007) as well as at 12 months of follow-up   . During In this multicenter, prospective observational study, we demonstrated that 1-dose BPG was inferior to the 3-dose regimen in achieving a 4-fold or greater decline in RPR titers at 12 months of follow-up since a higher failure rate and a shorter time to treatment failure were noted in the 1-dose group. The better serological response was associated with higher RPR titers (RPR≥32) at baseline, secondary syphilis, and 3-dose BPG therapy. Although not statistically significant, we found a trend that a higher serologic response rate was associated with higher CD4 cell counts.In HIV-infected patients with syphilis, the serological response rates to BPG ranged from 70.4% to 91.8% in previous retrospective studies that were conducted in the cART era In this study, we failed to demonstrate that the serological response of the 1-dose group was non-inferior to that of the 3-dose group during the 12-month follow-up. The subgroup analysis demonstrated the consistency with overall serological response favoring 3 weekly doses of BPG except for the subgroups of patients who presented with primary syphilis and RPR titers <32 . The resIn our study, the patients who failed to achieve a serological response often had a 4-fold increase of RPR titer after ever achieving a serological response during the 12-month follow-up period or experienced primary or secondary syphilis suggesting reinfection with syphilis, which was more frequently observed in the patients who received 1 dose of BPG than those who received 3 weekly doses. Given the long interval between treatment administration and treatment failure, our findings of a lower response rate to 1 dose BPG therapy than to 3 weekly doses may result from higher rates of reinfection with syphilis, suggesting that more intensive safe-sex counseling is needed to be implemented in this high-risk population.The strengths of our study include that it is a prospective observational study with a large sample size and the two groups of patients had similar baseline characteristics , includiP = 0.004). Therefore, we believe that more episodes of reinfection could contribute to the higher failure rate in the 1-dose group. Fourth, 94% of the patients in our study were MSM, and therefore our results may not be generalizable to other risk groups. Last, we did not perform cerebrospinal fluid study in patients with higher RPR titers or lower CD4 counts, as suggested by previous investigators There are several limitations of our study, however. First of all, this is not a randomized clinical trial and the decision to give 1 dose or 3 doses of BPG depended on the assessment of physicians who might prefer to give the more enhanced, 3 doses of BPG to patients who were considered at a higher risk for recurrent syphilis or treatment failure such as a previous history of syphilis, higher RPR titers, early latent syphilis, or lower CD4 counts, higher plasma HIV RNA loads, a history of prior opportunistic infections and more advanced HIV disease. However, there were no statistically significant differences in the baseline characteristics when treatment for syphilis was administered between the two study groups in our study. Second, nearly one fourth of the patients had missing RPR titers at 6 and 12 months following treatment. However, if we analyze the patients with available 6-month and 12-month RPR titers, the response rate is still nearly the same between 1-dose and 3-doses BPG in 12-month . Third, In summary, we failed to demonstrate the non-inferiority of 1 dose of BPG to 3 weekly doses of BPG for treatment of early syphilis in HIV-infected patients. A substantial rate of treatment failure due to reinfection in both groups suggests that counseling for risk behavior modification should be integral component of management of HIV-infected patients with early syphilis.Figure S1Trends of the proportions of the patients receiving 1 dose or 3 weekly doses of benzathine penicillin G between 2007 and 2012 before and after revision of Sexually Transmitted Diseases Treatment Guidelines by the US Centers for Disease Control and Prevention in 2010. The number inside the bar indicates the number of the patients receiving 1 dose (stippled) or 3 weekly doses (gray) of benzathine penicillin G.(TIFF)Click here for additional data file.Figure S2The serological response rates of 1 or 3 doses of benzathine penicillin G therapy before and after the revision of Sexually Transmitted Diseases Treatment Guidelines in 2010.(TIFF)Click here for additional data file.Figure S3The causes of treatment failure for the two groups of patients at 12 months of treatment. The numbers inside the bars indicate the cases of treatment failure.(TIFF)Click here for additional data file.Figure S4Forest plot showing the serological response rates in different subgroups of patients receiving 1 or 3 doses of benzathine penicillin G at 6 months of follow-up.(TIFF)Click here for additional data file.Table S1Comparisons of clinical characteristics of patients with missing rapid plasma reagin values and those without missing values at 6 months of follow-up.(DOCX)Click here for additional data file.Table S2Comparisons of clinical characteristics of patients with missing rapid plasma reagin values and those without missing values at 12 months of follow-up.(DOCX)Click here for additional data file.Table S3Factors associated with serological response in the patients who received 1 dose or 3 doses of benzathine penicillin G at 6 months of follow-up in univariate and multivariate analysis.(DOC)Click here for additional data file.