Two patients with primary resistances at inclusion and another infected with a group O virus were excluded from the analysis of the emergence of HIV drug resistance. A total of 59 patients had viral loads ≥5000 copies per milliliter on 2 consecutive samples or on their last available sample. Resistance testing was performed on the samples of all these patients. Resistance emerged in 12 men (9.0%) and 33 women (10.2%). The corresponding incidence rate was 6.2 per 100 person-years (95% CI: 3.5 to 11.0) and 6.4 per 100 person-years (95% CI: 4.5 to 9.0), respectively. Gender was not associated with the emergence of resistance in univariate analysis [time ratio (TR): 0.98, 95% CI: 0.60 to 1.62, P = 0.950] or in multivariate analysis [adjusted time ratio (aTR): 0.86, 95% CI: 0.51 to 1.44, P = 0.558; see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A661]. There were no differences between both genders at the time of resistance emergence in number of nonnucleoside reverse transcriptase inhibitor–associated mutations (median 2 IQR: 1–3 in men versus 1 IQR: 1–2 in women, P = 0.397), nucleoside reverse transcriptase inhibitor–associated mutations (median 0 IQR: 0–1 in men versus 0 IQR: 0–0 in women, P = 0.625), or the M184V mutation [9 (75%) of 12 men versus 20 (61%) of 33 women, P = 0.419].
The median increase in CD4 cell count from ART initiation was 157 cells per microliter (IQR: 62–232) at month 6, 131 cells per microliter (IQR: 57–206) at month 12, 209 cells per microliter (IQR: 98–262) at month 18, and 184 cells per microliter (IQR: 77–288) at month 24 in men. In women, the median increase was 163 cells per microliter (IQR: 66–260), 173 cells per microliter (IQR: 89–261), 203 cells per microliter (IQR: 100–321), and 244 cells per microliter (IQR: 114–351), respectively. By univariate analysis, male gender was associated with a lower CD4 recovery (β: −35.1, 95% CI: −66.4 to −3.9, P = 0.028). By multivariate analysis, there was a significant interaction between gender and follow-up time point, meaning that the trajectory of CD4 recovery differed between men and women. On average, men gained 25.3 (95% CI: −15.7 to 66.3, P = 0.227) fewer CD4 cells than their female counterparts at month 12, 20.2 (95% CI: −20.9 to 61.2, P = 0.335) fewer CD4 cells at month 18, and 58.7 (95% CI: 16.6 to 100.8, P = 0.006) fewer CD4 cells at month 24, after adjustment for age, body mass index, hemoglobin level, antiretroviral regimen, and adherence (Table 4).
Thirty-two men (23.7%) and 44 women (13.6%) died. Mortality rate was 15.4 per 100 person-years (95% CI: 10.9 to 21.8) in men and 8.1 per 100 person-years (95% CI: 6.0 to 10.8) in women. Survival in men was 85.0%, 83.4%, 78.5%, and 75.1% at months 6, 12, 18, and 24, respectively. In women, survival was 89.3%, 88.6%, 86.9%, and 85.9%, respectively. By univariate analysis, male gender was associated with a lower survival (TR: 0.25, 95% CI: 0.08 to 0.79, P = 0.018). The multivariate analysis confirmed this finding (aTR: 0.30, 95% CI: 0.12 to 0.78, P = 0.014) after adjustment for age, body mass index, hemoglobin level, antiretroviral regimen, and adherence (Table 4).
In men, most deaths were related to infectious diseases (n = 23, 71.9%) including pulmonary infections (n = 11), enterocolitis (n = 4), cryptococcosis (n = 3), sepsis (n = 2), fulminant hepatitis B (n = 1), oesophageal candidosis (n = 1), and malaria (n = 1). Noninfectious causes of death included anemia (n = 2), hepatocellular carcinoma (n = 2), wasting syndrome (n = 2), Kaposi sarcoma (n = 1), and stroke (n = 1). In women, infectious causes of death (n = 35, 79.5%) included pulmonary (n = 12) and extrapulmonary (n = 3) tuberculosis, enterocolitis (n = 9), encephalopathy (n = 7), sepsis (n = 3), and chronic diarrhea (n = 1). Noninfectious causes of death included anemia (n = 2), Kaposi sarcoma (n = 2), wasting syndrome (n = 1), psychosis (n = 1), and rupture of oesophageal varices (n = 1).
Thirty-seven men (27.4%) and 55 women (17.0%) had disease progression to death or to a WHO stage 4 event. The incidence rate of disease progression was 18.6 per 100 person-years (95% CI: 13.5 to 25.6) in men and 10.4 per 100 person-years (95% CI: 8.0 to 13.6) in women. Survival without WHO stage 4 event after 6, 12, 18, and 24 months of treatment was 82.0%, 79.6%, 74.7%, and 71.3% in men and 86.8%, 85.5%, 83.5%, and 82.5% in women, respectively. Male gender was significantly associated with a faster disease progression in both univariate analysis (TR: 0.30, 95% CI: 0.10 to 0.88, P = 0.028) and multivariate analysis (aTR: 0.27, 95% CI: 0.09 to 0.79, P = 0.017; Table 4).
This study in rural district hospitals in Cameroon showed a higher risk of ART failure in men than in women. Importantly, the worse therapeutic response in men was not related to a gender difference in adherence to ART. The vulnerability of men was also not related to a difference in HIV disease stage at the time of treatment initiation.
Our findings add to the growing body of evidence to suggest that men who access ART in sub-Saharan Africa are more at risk of therapeutic failure than women, independently of their later initiation of treatment.11,13,15,17–20,23–40,49 Moreover, we studied a wide range of ART outcomes, including virologic failure, immune reconstitution, mortality, and disease progression, and all results were concordant. In contrast, the previous studies only focused on some of these outcomes. It is worth noting that some studies did not show gender differences in therapeutic failure but that, to our knowledge, no studies have found a higher risk of failure in women in this setting.12,18,21,22,50,51
A crucial finding of our study is that adherence to ART did not explain the male vulnerability to therapeutic failure. Indeed, there was no gender difference in adherence and the analyses of ART effectiveness were adjusted for adherence. Although the measurement of adherence is subject to biases, the validity of our finding seemed good. First, our data on patient self-reported adherence were obtained using a validated questionnaire constructed to limit both recall and social desirability bias.44,45 In addition, the sensitivity to detect nonadherent behaviors was improved by incorporating adherence data reported to physicians or nurses at the clinical visits. Because the patterns of adherence are major determinants of ART effectiveness, we used an adherence scale that distinguishes different levels of adherence and treatment interruptions. Studies have indeed shown that low adherence and treatment interruptions for more than 2 days are independently associated with increased risk of therapeutic failure.46 Second, the absence of gender difference in adherence was observed with both the patient self-reports and the measurement of antiretroviral plasma concentrations. Third, the data from self-reports were associated with those from plasma concentrations. Finally, the data from both methods were associated with virologic effectiveness. A gender difference in reporting adherence was unlikely as suggested by the comparable antiretroviral plasma concentrations between men and women.
Altogether, our findings highlighted the higher risk of therapeutic failure in men independently of their adherence behaviors. Similarly, a cross-sectional survey in Cameroon had found a worse immunologic response in men despite a better adherence to ART.33 In Tanzania, where men were less likely to adhere to clinical visits than women (adherence to ART was unfortunately not reported), mortality and immunologic failure remained higher in men when the analyses were restricted to the period of good adherence for all patients.15 Although they did not compare adherence between men and women, other studies found that men were more at risk of therapeutic failure after adjustment for adherence.25,30,31 In contrast, the higher mortality in South African men observed in univariate analysis did not persist after adjustment for adherence and baseline characteristics; in this study, men were less likely to have a pharmacy-claim adherence above 80% than women.41
Gender differences in pharmacokinetic and pharmacodynamic profiles of antiretroviral drugs might explain the vulnerability of men to ART failure.52,53 Higher concentrations of antiretroviral drugs, which favour the ART efficacy,54,55 have thus been observed in women than in men. However, antiretroviral plasma concentrations in our study were comparable between men and women (although the former had higher bodyweight and body mass index).
The vulnerability of men to ART failure could also be related to intrinsic biologic differences between both genders. Because male hormones downregulate the thymic function,56 men may have a lesser ability to regenerate their CD4 stock while on ART. Also, Mathad et al57 suggested that men had a less favorable immune profile before ART with significantly higher C-reactive protein, lipopolysaccharide, and soluble CD14 than women. Other experts suggested differential immune senescence and CCR5 expression.
A strength of our study is that it was performed in a large cohort with regular follow-up and record of adherence, biologic and clinical data. The proportion of patients lost to follow-up was also limited and comparable between men and women. In contrast, in addition to the limitation related to the difficulty for measuring adherence as underlined above, the fact that our data were recorded in the context of a trial may give rise to a problem of representativeness of our study population and procedures. Specifically, people participating in a trial may tend to be more adherent to ART than patients followed up in the routine clinical setting. Nevertheless, the main demographic and medical characteristics, and the adherence behaviors of our patients, were comparable with those followed up in the Cameroonian national AIDS program, and our study procedures incorporated the good clinical practices required in such settings.33 Regarding the analysis of resistance, the statistical power was relatively low because 45 patients only developed resistance. This may have limited our ability to find statistical associations, for instance between low adherence and resistance because the number of patients with low adherence was especially small. Finally, although liver profiles were comparable between men and women, it could have been interesting to know the patients' status regarding the chronic viral hepatitis B and/or C.
In conclusion, this study provides important evidence that African men are more vulnerable to ART failure than women and that the male vulnerability extends beyond adherence issues. Additional studies are needed to determine the causes for this male vulnerability, including by investigating biologic/hormonal hypotheses, to optimize HIV care. However, personalized adherence support remains crucial.
The authors thank all the patients and staff of the district hospitals who participated in the study.
Stratall ANRS 12110/ESTHER Study Group:
M. Biwolé-Sida, C. Kouanfack, and S. Koulla-Shiro (Central Hospital, Yaoundé, Cameroon); A. Bourgeois, E. Delaporte, C. Laurent, and M. Peeters (IRD, University Montpellier 1, UMI 233, Montpellier, France); G. Laborde-Balen (French Ministry of Foreign Affairs, Yaoundé, Cameroon); M. Dontsop, S. Kazé, and J.-M. Mben (IRD, Yaoundé, Cameroon); A. Aghokeng, M.G. Edoul, E. Mpoudi-Ngolé, and M. Tongo (Virology Laboratory, IMPM/CREMER/IRD-UMI 233, Yaoundé, Cameroon); S. Boyer, M.P. Carrieri, F. Marcellin, J.-P. Moatti, and B. Spire (INSERM, IRD, University Marseille, UMR 912, Marseille, France); C. Abé, S.-C. Abega, C.-R. Bonono, H. Mimcheu, S. Ngo Yebga, and C. Paul Bile (IRSA, Catholic University of Central Africa, Yaoundé, Cameroon); S. Abada, T. Abanda, J. Baga, P. Bilobi Fouda, P. Etong Mve, G. Fetse Tama, H. Kemo, A. Ongodo, V. Tadewa, and H.D. Voundi (District Hospital, Ayos, Cameroon); A. Ambani, M. Atangana, J.-C. Biaback, M. Kennedy, H. Kibedou, F. Kounga, M. Maguip Abanda, E. Mamang, A. Mikone, S. Tang, E. Tchuangue, S. Tchuenko, and D. Yakan (District Hospital, Bafia, Cameroon); J. Assandje, S. Ebana, D. Ebo'o, D. Etoundi, G. Ngama, P. Mbarga Ango, J. Mbezele, G. Mbong, C. Moung, N. Ekotto, G. Nguemba Balla, G. Ottou, and M. Tigougmo (District Hospital, Mbalmayo, Cameroon); R. Beyala, B. Ebene, C. Effemba, F. Eyebe, M.-M. Hadjaratou, T. Mbarga, M. Metou, M. Ndam, B. Ngoa, E.B. Ngock, and N. Obam (District Hospital, Mfou, Cameroon); A.M. Abomo, G. Angoula, E. Ekassi, Essama, J.J. Lentchou, I. Mvilongo, J. Ngapou, F. Ntokombo, V. Ondoua, R. Palawo, S. Sebe, E. Sinou, D. Wankam, and I. Zobo (District Hospital, Monatélé, Cameroon); B. Akono, A.L. Ambani, L. Bilock, R. Bilo'o, J. Boombhi, F.X. Fouda, M. Guitonga, R. Mad'aa, D.R. Metou'ou, S. Mgbih, A. Noah, M. Tadena, and Ntcham (District Hospital, Nanga Eboko, Cameroon); G. Ambassa Elime, A.A. Bonongnaba, E. Foaleng, R.M. Heles, R. Messina, O. Nana Ndankou, S.A. Ngono, D. Ngono Menounga, S.S. Sil, L. Tchouamou, and B. Zambou (District Hospital, Ndikinimeki, Cameroon); R. Abomo, J. Ambomo, C. Beyomo, P. Eloundou, C. Ewole, J. Fokom, M. Mvoto, M. Ngadena, R. Nyolo, C. Onana, and A. Oyie (District Hospital, Obala, Cameroon); P. Antyimi, S. Bella Mbatonga, M. Bikomo, Y. Molo Bodo, S. Ndi Ntang, P. Ndoudoumou, L. Ndzomo, S.O. Ngolo, M. Nkengue, Nkoa, and Y. Tchinda (District Hospital, Sa'a, Cameroon).
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HIV; sub-Saharan Africa; gender; antiretroviral treatment; outcomes
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